CoChat
Sign Up
Cited by 1,443Psoriasis: Treatment and PathogenesisCytokine Signaling Pathways and InteractionsT-cell and B-cell Immunology

The IL-17 Family of Cytokines in Health and Disease

Open access
McGeachy, Mandy J., Cua, Daniel J., Gaffen, Sarah L.·2019·Immunity
DOI 10.1016/j.immuni.2019.03.021PMC PMC6474359
Open this paper in CoChat — free accountOpen PDF

Abstract

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25th anniversary of its discovery. While less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys the IL-17 cytokine family, focusing on IL-17A and its context-dependent roles in host defense, tissue repair, autoimmunity, and cancer. It argues that IL-17 is not simply pro-inflammatory but can be protective or pathogenic depending on tissue, microbial context, and signaling environment.

Key findings

  • IL-17A is the best-studied family member and is central to the IL-23–IL-17 axis, with therapeutic blockade showing strong efficacy in psoriasis: IL-17 and IL-23 inhibitors achieved complete PASI 100 responses in roughly 40–80% of patients.
  • Therapeutic results diverge by disease: IL-17 blockade is effective in psoriatic arthritis and ankylosing spondylitis, but has limited benefit in rheumatoid arthritis and Crohn’s disease, where some patients experienced exacerbations or increased inflammation markers.
  • IL-17 has protective roles at barrier surfaces and in injured tissues, including antifungal and antibacterial immunity, wound healing, and maintenance of intestinal epithelial tight junctions, while chronic or misplaced IL-17 responses drive tissue damage, bone erosion, fibrosis, and tumor-promoting inflammation.
  • In colorectal cancer, IL-17 signatures associate with worse outcomes, and IL-17 may promote angiogenesis and resistance to anti-VEGF therapy; only about 8% of colon cancer patients have mismatch-repair deficiency/MSI and respond to anti-PD1, whereas MSS patients show elevated IL-17 and are largely unresponsive.

Methods

  • Narrative review of the IL-17 family, with emphasis on IL-17A, synthesizing mechanistic, mouse-model, human genetic, and clinical trial literature.
  • No primary experimental data, sample, or systematic search strategy are reported; the analysis is a conceptual synthesis of published findings.
  • The review covers IL-17 structure and signaling, functions of IL-17B–F, IL-17A in barrier and non-barrier tissues, post-transcriptional regulation, and cancer pathogenesis.

Limitations

  • The paper states that understanding of IL-17 biology remains in its infancy, especially regarding synergistic signaling, cytokine tuning, and microbial influences.
  • It notes that IL-17B, IL-17C, and IL-17D are poorly studied, partly due to limited tools, and that orphan ligands and receptors remain in the family.
  • Evident from the text: as a narrative review, it does not provide a systematic evidence appraisal, and its strong focus on IL-17A limits detailed coverage of other family members.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.immuni.2019.03.021

Cites

198 of 198 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 215 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    IL-17A and its first receptor, IL-17RA, are distinct in sequence from other known mammalian cytokines.

    “both the ligand and receptor were distinct in sequence from other known mammalian cytokines.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gaffen, 2011 source

      Not checked in the free run.

    • cites Yao et al., 1995a

      Not checked in the free run.

  • Interpretationnone given

    IL-17A has a pro-inflammatory role in autoimmune disease.

    “IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The functions of IL-17 are more nuanced than simply turning on inflammation.

    “the functions of IL-17 are far more nuanced than simply turning on inflammation.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    IL-17 has context- and tissue-dependent roles in maintaining health during injury, physiological stress, and infection.

    “IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress and infection.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The IL-17 receptor family is a distinct subclass with a shared cytoplasmic SEFIR motif distantly related to the TIR domain.

    “the IL-17 receptor family comprises a distinct subclass of receptors characterized by a shared cytoplasmic motif termed a “SEFIR”, which has a distant relationship with the TIR domain”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Novatchkova et al., 2003 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 7
  • May combine two claims. 64
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The IL-17 cytokine family is evolutionarily ancient and is present in jawless fish, Mollusca, and sea urchins.

    “present in species as early as jawless fish as well as Mollusca and sea urchins”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Buckley et al., 2017 source

      Not checked in the free run.

    • cites Han et al., 2015 source

      Not checked in the free run.

    • cites Novatchkova et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 is elevated in human inflammatory or autoimmune diseases and is expressed in a non-canonical T helper cell population.

    “this cytokine was elevated in human inflammatory or autoimmune diseases and was expressed in a non-canonical T helper cell population”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Albanesi et al., 1999 source

      Not checked in the free run.

    • cites Antonysamy et al., 1999 source

      Not checked in the free run.

    • cites Infante-Duarte et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The IL-23-IL-17 axis is a critical driver of autoimmune disease, first in mouse models and later validated in humans by GWAS and clinical blockade.

    “The so-called “IL-23-IL-17 axis” was found to function as a critical driver of autoimmune disease”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Duerr et al., 2006 source

      Not checked in the free run.

    • cites Harrington et al., 2005 source

      Not checked in the free run.

    • cites Langrish et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 is produced by CD8+ Tc17 cells and innate lymphocyte subsets including γδ T, NKT, ILC3, and natural Th17 cells.

    “IL-17 was subsequently shown to be produced by other cell populations, such as CD8+ (Tc17) cells as well as various subsets of innate lymphocytes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cua and Tato, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17R signaling begins with recruitment of Act1, which contains a SEFIR domain required for IL-17R-Act1 association.

    “The initial event in IL-17R signaling is recruitment of Act1 (aka CIKS), a multifunctional signaling protein that also contains a SEFIR domain necessary for IL-17R-Act1 association”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Liu et al., 2011a

      Not checked in the free run.

    • cites Qian et al., 2007 source

      Not checked in the free run.

    • cites Sonder et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IκBζ is implicated in psoriasis both genetically and functionally.

    “IκBζ is implicated in psoriasis both genetically and functionally”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Johansen et al., 2015 source

      Not checked in the free run.

    • cites Tsoi et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17A has sequence homology with an open reading frame in Herpesvirus saimiri but not with other known cytokine families.

    “showed unexpected sequence homology with an open reading frame in Herpesvirus saimiri, a T cell tropic γ-herpesvirus, but not with other known cytokine families”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gaffen, 2011 source

      Not checked in the free run.

    • cites Yao et al., 1995a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 induces proliferative signaling in keratinocytes through Act1, contributing to psoriasis and possibly skin tumorigenesis.

    “IL-17 also induces proliferative signaling in keratinocytes through Act1, a major facet of its impact in psoriasis and perhaps also explaining its involvement in skin tumorigenesis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chiricozzi and Krueger, 2013

      Not checked in the free run.

    • cites Ha et al., 2014

      Not checked in the free run.

    • cites Langowski et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In keratinocytes, Syk kinase binds Act1 and TRAF6 and functions upstream of NF-κB to induce CCL20, potentially driving a feed-forward Th17 inflammation circuit.

    “The Syk kinase was reported to bind to Act1 and TRAF6 and thus function upstream of NF-κB leading to expression of the chemokine CCL20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wu et al., 2015c

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TRAF6 promotes activation of MAPK/AP1 pathways and the C/EBPβ and δ transcription factors.

    “TRAF6 also promotes activation of MAPK/AP1 pathways and the C/EBPβ and δ transcription factors”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chang et al., 2006 source

      Not checked in the free run.

    • cites Maitra et al., 2007 source

      Not checked in the free run.

    • cites Qian et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17B increases during intestinal inflammation and promotes neutrophil migration upon intraperitoneal administration, suggesting a pro-inflammatory role.

    “IL-17B was originally found to increase during intestinal inflammation and to promote neutrophil migration upon intraperitoneal administration, suggesting a pro-inflammatory role”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bie et al., 2017a

      Not checked in the free run.

    • cites Shi et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NF-κB upregulates IκBζ and Bcl3, which promote expression of IL-17-NF-κB driven pro-inflammatory and anti-microbial genes.

    “NF-κB subsequently upregulates expression of IκBζ and Bcl3, noncanonical members of the NF-κB family that in turn promote expression of various IL-17-NF-κB driven pro-inflammatory and anti-microbial genes”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Karlsen et al., 2010 source

      Not checked in the free run.

    • cites Ruddy et al., 2004 source

      Not checked in the free run.

    • cites Tohyama et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IL-17 regulates NF-κB and CCL20 through CARMA2, encoded by CARD14, which interacts with Act1 and TRAF6.

    “IL-17 was suggested to regulate NF-κB and CCL20 through CARMA2, encoded by CARD14”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Tsoi et al., 2012 source

      Not checked in the free run.

    • cites Wang et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking Act1 phenocopy Il17ra−/− mice, and humans with null ACT1 mutations have fungal susceptibility phenotypes identical to those lacking IL17RA or IL17RC.

    “Mice lacking Act1 phenocopy Il17ra−/− mice, and rare humans with null mutations in ACT1 have identical phenotypes with respect to fungal susceptibility as those lacking IL17RA or IL17RC”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Conti and Gaffen, 2015

      Not checked in the free run.

    • cites Li et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    During helminth infection, intestinal tuft cells produce large amounts of IL-25, which promotes ILC2 IL-13 secretion and programs epithelial crypt progenitors toward goblet and tuft cells, enhancing mucus production for worm expulsion.

    “During parasitic helminth infection, intestinal tuft cells produce large amounts of IL-25. This in turn promotes ILC2 cells to secretion IL-13, which programs epithelial crypt progenitors to differentiate toward goblet and tuft cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-17C promotes antimicrobial protective responses and barrier maintenance in skin and intestine.

    “IL-17C promotes anti-microbial protective responses and barrier maintenance in skin and intestine”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ramirez-Carrozzi et al., 2011 source

      Not checked in the free run.

    • cites Song et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-25 is produced by a subset of thymic epithelial cells with chemosensory functions, providing antigen for TCR selection and development of iNKT-2 cells.

    “IL-25 was also shown to be produced by a subset of thymic epithelial cells that has chemosensory functions, similar to the intestinal tuft cells”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bornstein et al., 2018 source

      Not checked in the free run.

    • cites Miller et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IL-25 is a barrier surface cytokine whose production is largely regulated by environmental cues.

    “These results indicate that IL-25 is a “barrier surface” cytokine and its production is largely regulated by environmental cues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-17F contributes to inflammatory responses and barrier protection, as shown by heightened susceptibility to chronic mucocutaneous candidiasis in humans with autosomal dominant IL17F deficiency.

    “IL-17F contributes to inflammatory responses and protection at barrier surfaces, as evidenced by heightened susceptibility to chronic mucocutaneous candidiasis in humans with an autosomal dominant IL17F deficiency”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Puel et al., 2011b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17D is expressed in many healthy tissues and increases in tumors and during viral infection.

    “It is expressed in a wide variety of healthy tissues, and has been found to increase in tumors and during viral infection”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Saddawi-Konefka et al., 2016 source

      Not checked in the free run.

    • cites Seelige et al., 2017 source

      Not checked in the free run.

    • cites Starnes et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IL-17C is produced by epithelial cells rather than immune cells and acts as a rapid local autocrine response to epithelial injury.

    “IL-17C is produced by epithelial cells rather than immune cells, hence acts as a rapid local autocrine response to epithelial injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-25 gene expression is elevated after Aspergillus and Nippostrongylus infection in lung and gut, and IL-25 promotes epithelial hyperplasia, mucus secretion, and airway hyperreactivity.

    “Early studies showed that IL-25 gene expression was elevated following Aspergillus and Nippostrongylus infection in the lung and gut, and that IL-25 promoted epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Owyang et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17A, IL-17AF, and IL-17F trigger qualitatively similar signaling pathways, but IL-17A homodimers are far more potent than IL-17F homodimers, with IL-17AF intermediate.

    “IL-17A, -AF and -F trigger qualitatively similar signaling pathways, however IL-17A homodimers induce a far more potent signal compared to IL-17F homodimers, with IL-17AF thought to be intermediate signaling strength”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chang and Dong, 2007

      Not checked in the free run.

    • cites Wright et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-25 treatment elevates IL-13 and suppresses IL-1, IL-6, and IL-23 production by activated dendritic cells.

    “IL-25 treatment elevated production of IL-13 and suppressed expression of IL-1, IL-6, and IL-23 by activated dendritic cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kleinschek et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17F and IL-17A are co-expressed on linked genes and are usually co-produced by Type 17 cells.

    “IL-17F and IL-17A are co-expressed on linked genes and are usually co-produced by Type 17 cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Akimzhanov et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disease exacerbations occurred in some Crohn's patients treated with secukinumab, and increased serum C-reactive protein occurred in patients receiving brodalumab.

    “disease exacerbations observed in some patients treated with secukinumab (anti-IL-17) (Hueber et al., 2012), and increased serum C-reactive protein, an indicator of inflammation, in patients receiving brodalumab (anti-IL-17RA) (Targan et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hueber et al., 2012 source

      Not checked in the free run.

    • cites Targan et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 induces IL-6 and G-CSF, which promote myeloid-driven innate inflammation.

    “IL-17 induces IL-6 and G-CSF, cytokines that promote myeloid-driven innate inflammation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gaffen et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 production is increased during inflammatory bowel disease, yet healthy intestine contains significant populations of IL-17-producing cells.

    “IL-17 production is increased during inflammatory bowel disease (Kleinschek et al., 2009), yet healthy intestine also contains significant populations of IL-17-producing cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kleinschek et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mouse studies show that colitis-associated epithelial injury and intestinal leakage are exacerbated in the absence of IL-17 signaling, and IL-17 helps maintain the epithelial tight-junction barrier during inflammation.

    “mouse studies showed that colitis-associated epithelial injury and intestinal leakage can be exacerbated in absence of IL-17 signaling, and revealed that IL-17 serves a beneficial role in the intestinal epithelium by helping to maintain the epithelial tight-junction barrier during inflammation”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lee et al., 2015 source

      Not checked in the free run.

    • cites Maxwell et al., 2015 source

      Not checked in the free run.

    • cites Whibley and Gaffen, 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In psoriatic skin lesions, dysregulated IL-17 production or uncontrolled responses to IL-17 signaling promote pathogenic inflammation.

    “In psoriatic skin lesions, dysregulated IL-17 production or uncontrolled responses to IL-17 signaling promote pathogenic inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The pro-proliferative role of IL-17 likely contributes to pathogenic effects in psoriasis and potentially skin cancer.

    “this pro-proliferative role likely contributes to the pathogenic effects of IL-17 in psoriasis, as well as potentially in skin cancer”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chen et al., 2019 source

      Not checked in the free run.

    • cites Lai et al., 2012 source

      Not checked in the free run.

    • cites Langowski et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mechanical gum injury from chewing hard foods increases gingival IL-17, and increased IL-17 contributes to periodontitis and bone erosion during aging.

    “the mechanical gum injury caused by chewing of hard foods increases gingival IL-17 levels, and increased IL-17 then contributes to periodontitis and bone erosion during aging”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dutzan et al., 2017b

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The direct link between IL-23 and IL-17 seen in psoriasis does not appear to extend to IBD, where IL-23 likely drives additional effectors and IL-17's protective functions counterbalance its pathogenic potential.

    “Hence the direct link between IL-23 and IL-17 observed in psoriasis does not appear to extend to inflammatory bowel disease, where IL-23 is likely driving an armory of additional effector molecules such that the specific protective functions of IL-17 in the injured gut apparently counterbalance its pathogenic potential.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oral IL-17 production is required to prevent outgrowth of gingivitis-causing bacteria in acute infections and protect against bacterial inflammation-induced bone loss.

    “oral IL-17 production is required to prevent outgrowth of gingivitis-causing bacteria in acute infections (Yu et al., 2007) and thus protect against bacterial inflammation-induced bone loss.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yu et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 promotes glomerulonephritis after immune complex deposition in the kidney and is thought to contribute to lupus renal disease.

    “IL-17 promotes glomerulonephritis following immune complex deposition in the kidney, and is thus thought to contribute to lupus renal disease”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pisitkun et al., 2012 source

      Not checked in the free run.

    • cites Ramani et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased systemic IL-17 during pregnancy leads to autism-like behaviors in pup offspring, which can be regulated by maternal microbiota.

    “Increased systemic IL-17 during pregnancy leads to development of autism-like behaviors in pup offspring (Choi et al., 2016), which can also be regulated by maternal microbiota (Kim et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Choi et al., 2016 source

      Not checked in the free run.

    • cites Kim et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Th17 cells exacerbate depression-like symptoms in mice and infiltrate the prefrontal cortex and hippocampus in depressed mice compared to controls.

    “Th17 cells exacerbated depression-like symptoms in mice, and infiltrated the pre-frontal cortex and particularly hippocampus in depressed mice compared to controls”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Beurel et al., 2013 source

      Not checked in the free run.

    • cites Beurel and Lowell, 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although joints are sterile, dysregulated gut microbiota are found in autoimmune subjects including rheumatoid arthritis and contribute to arthritis susceptibility in mice.

    “Although joints are sterile tissues, dysregulated gut microbiota are found in autoimmune subjects, including those with rheumatoid arthritis (RA) (Scher et al., 2013), and have been demonstrated to contribute to arthritis susceptibility in mice”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Scher et al., 2013 source

      Not checked in the free run.

    • cites Maeda et al., 2016 source

      Not checked in the free run.

    • cites Wu et al., 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Joints and barrier surfaces share relatively high exposure to mechanical stress, which may be analogous to oral tissues where mastication drives IL-17-induced damage.

    “Joints and barrier surfaces also have in common a relatively high exposure to mechanical stress during routine use, which may be analogous to oral tissues where mastication drives IL-17-induced damage”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dutzan et al., 2017a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 blockade is effective in psoriatic arthritis and ankylosing spondylitis.

    “IL-17 blockade was effective in psoriatic arthritis (PsA) (McInnes et al., 2014; Mease and McInnes, 2016) as well as ankylosing spondylitis (AS)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McInnes et al., 2014 source

      Not checked in the free run.

    • cites Mease and McInnes, 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 activates CNS-resident cells, causing neuronal hyperexcitability, chemokine and cytokine production by astrocytes and oligodendrocytes, and proliferation and death of oligodendrocyte precursors.

    “IL-17 activates CNS-resident cells causing hyperexcitability of neurons (Siffrin et al., 2010), production of chemokines and cytokines by astrocytes and oligodendocytes and proliferation and ultimately death of oligodendrocyte precursors (Kang et al., 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Siffrin et al., 2010 source

      Not checked in the free run.

    • cites Kang et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Most IL-17 signaling occurs in non-hematopoietic cells expressing the heterodimeric IL-17RA:IL-17RC receptor.

    “the predominance of IL-17 signaling occurs in none-hematopoietic cells expressing the heterodimeric IL-17RA:IL-17RC receptor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-17 is protective when the kidney is injured by mechanical obstruction or systemic Candida albicans infection.

    “IL-17 is protective when the kidney is injured by mechanical obstruction or systemic Candida albicans infection”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ramani et al., 2016 source

      Not checked in the free run.

    • cites Ramani et al., 2018b

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IL-17 is not simply a catch-all master inflammatory factor, and tissue- and immune-specific factors modulate its role during inflammation.

    “These findings collectively indicate that IL-17 is a not simply a ‘catch-all’ master inflammatory factor, and highlights the need to consider concomitant tissue- and immune-specific factors that modulate the role of IL-17 during inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It is difficult to extrapolate these brain findings to humans because human brain development and cognition are more complex than in mice.

    “It can be difficult to extrapolate these findings to humans, who have far more complex brain development and higher-order cognitive functioning than mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Traumatic or ischemic brain injury patients frequently develop dysbiosis during hospitalization, which could alter immune responses in the inflamed brain.

    “traumatic or ischemic brain injury patients frequently develop dysbiosis during hospitalization, which could alter immune responses in the inflamed brain”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Simon et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After kidney injury, IL-17 promotes bradykinin production by activating the kallikrein-kinin system in tubular epithelial cells, leading to MMP production that reduces fibrosis.

    “Following kidney injury, IL-17 promotes production of bradykinin by activating the kallikrein-kinin system in tubular epithelial cells (Ramani et al., 2018a), resulting in production of matrix metalloproteinases (MMPs) that reduce fibrosis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ramani et al., 2018a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the healthy state, IL-17 directly influences adipocyte metabolic function, increasing thermogenic enzyme expression and catecholamine sensitivity.

    “In the healthy state, IL-17 directly influences the metabolic function of adipocytes, increasing expression of thermogenic enzymes and sensitivity to catecholamine”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kohlgruber et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice deficient in IL-17 and fed regular chow gain increased fat mass with age, corresponding to a role for IL-17 in regulating glucose homeostasis and inhibiting adipogenesis.

    “Mice deficient in IL-17 and fed regular chow gain increased fat mass with age, corresponding to a role for IL-17 in regulating glucose homeostasis and inhibiting adipogenesis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ahmed and Gaffen, 2013

      Not checked in the free run.

    • cites Goswami et al., 2009 source

      Not checked in the free run.

    • cites Zuniga et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase II trials of secukinumab were reported successful in multiple sclerosis, but larger trials have not yet been initiated.

    “Phase II trials of secukinumab were reported to be successful in MS, but larger trials have yet to be initiated”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Patel and Kuchroo, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Circadian rhythm proteins, including melatonin and ERB-REV1a, regulate IL-17 production by Th17 cells.

    “proteins that control circadian rhythm in regulating IL-17 production by Th17 cells, including melatonin (Farez et al., 2015) and ERB-REV1a (Amir et al., 2018; Yu et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Farez et al., 2015 source

      Not checked in the free run.

    • cites Amir et al., 2018 source

      Not checked in the free run.

    • cites Yu et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased generation of IL-17-producing T cells during intestinal dysbiosis exacerbates CNS-targeted autoimmune disease and impairs recovery after brain ischemia.

    “Increased generation of IL-17-producing T cells during intestinal dysbiosis exacerbates central nervous system (CNS)-targeted autoimmune disease (Kumar et al., 2016) and impairs recovery following brain ischemia (stroke) (Benakis et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kumar et al., 2016 source

      Not checked in the free run.

    • cites Benakis et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17-deficient mice are susceptible to hypothermia despite increased total body fat and lipid droplet accumulation in adipocytes.

    “IL-17-deficient mice are susceptible to hypothermia, despite increased total body fat and accumulation of lipid droplets within adipocytes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kohlgruber et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MMP production is a characteristic response to IL-17, suggesting regulation of wound healing and fibrotic scarring could be a more general IL-17 function after injury.

    “Indeed, MMP production is a characteristic response to IL-17, suggesting that regulation of wound healing and fibrotic scarring could be a more general function of IL-17 following injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-17 promotes neuroinflammation and neurodegeneration in rodent models of multiple sclerosis and stroke.

    “IL-17 promotes neuroinflammation and neurodegeneration in rodent models of multiple sclerosis and stroke”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gelderblom et al., 2012 source

      Not checked in the free run.

    • cites Shichita et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regnase-1 and Roquins target different transcripts due to distinct subcellular localization: Regnase-1 targets actively translating transcripts during acute inflammation via polysomes, while Roquins target translationally inactive mRNAs.

    “However, Regnase-1 and Roquins are thought to target different transcripts by virtue of distinct subcellular localization: Regnase-1 targets actively-translating transcripts during acute inflammation by associating with polysomes, whereas Roquins tend to target translationally inactive mRNAs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mino et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, segmented filamentous bacteria (SFB) directly contact intestinal epithelial cells and promote intestinal IL-17 signature genes.

    “In mice, segmented filamentous bacteria (SFB) form direct physical contact with mouse intestinal epithelial cells and thereby promote intestinal IL-17 signature genes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ivanov et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The IL-17-driven pathway controlling RNA stability begins with Ikki (IKKe)-mediated phosphorylation of Act1, which directs Act1 to TRAF2 and TRAF5 and mobilizes multiple RBPs.

    “The IL-17-driven pathway that controls RNA stability is initiated by phosphorylation of Act1 by Ikki (IKKe), directing its association to TRAF2 and TRAF5. and mobilizing multiple RBPs”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Amatya et al., 2018 source

      Not checked in the free run.

    • cites Bulek et al., 2011 source

      Not checked in the free run.

    • cites Datta et al., 2010 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Regnase-1 and Roquins regulate IL-17 production by regulating Th17 differentiation, thereby tuning both production of and response to IL-17.

    “Interestingly, Regnase-1 and Roquins regulate IL-17 production by regulating Th17 differentiation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jeltsch et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regnase-1 degrades IL-17-induced mRNA transcripts and acts as a feedback inhibitor.

    “that degrades IL-17-induced mRNA transcripts, thus acting as a feedback inhibitor”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Akira, 2013 source

      Not checked in the free run.

    • cites Fu and Blackshear, 2017

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    IL-17 induces both positive and negative regulators of its own signaling pathways, creating complex feedback loops that can amplify or attenuate the inflammatory response.

    “IL-17 induces both positive and negative regulators of its own signaling pathways, resulting in complex feedback loops that can amplify or attenuate the inflammatory response”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For many tumor types, especially at mucosal barriers, Th1 and CD8+ cytotoxic T cell gene signatures are linked to better overall and relapse-free survival, whereas Th17 cell signatures correspond to worse patient outcomes.

    “For many tumor types, particularly at mucosal barriers, gene signatures of Th1 cells (IFNG, STAT1, TBX21) and CD8+ cytotoxic T cells (PRF1, GZMB) are linked to better overall and relapse-free patient survival, whereas Th17 cell signatures (RORC, IL17, IL23, STAT3) correspond to worse patient outcomes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tosolini et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 cooperates with TNFα, LPS, IL-1β, lymphotoxin, IFNγ, IL-13, TGFβ, FGF2, and a Candida albicans-derived pore-forming toxin.

    “In addition to synergizing with strong NF-κB activators such as TNFα, lipopolysaccharide (LPS), IL-1β and lymphotoxin, IL-17 cooperates with IFNγ (activator of STAT1), IL-13 (STAT6), TGFβ (SMADs), fibroblast growth factor (FGF)2 (Ras:Raf) and a Candida albicans-derived pore-forming toxin from Candida albicans (c-Fos)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Faour et al., 2003 source

      Not checked in the free run.

    • cites Miossec, 2003 source

      Not checked in the free run.

    • cites Ruddy et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regnase-1 binds similar RNA sites to Roquin-1 and Roquin-2, which also restrict IL-17 signaling by degrading target genes.

    “Regnase-1 binds similar RNA sites to the RBPs Roquin-1 and Roquin-2, which also restrict IL-17 signaling by degrading target genes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jeltsch et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The composition of the gut microbiome likely alters the balance between favorable Th1/CD8+ cytotoxic T cell responses and unfavorable tolerogenic or Th17 immune responses, and could mediate patient response to immunotherapy.

    “Nevertheless, these results suggest that the composition of the gut microbiome likely alters the balance between favorable Th1 and CD8+ cytotoxic T cell response versus unfavorable tolerogenic or Th17 immune responses and could thus mediate patient response to immunotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that patient, anti-IL-17 cleared the psoriasis but the cancer progressed.

    “Anti-IL-17 was administered and cleared the psoriasis, but unfortunately the cancer progressed”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Esfahani and Miller, 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many patients with colorectal carcinoma and DNA mismatch repair deficiency are highly responsive to checkpoint blockade treatment, where anti-PD1 can reactivate tumor-infiltrating CD8+ cytotoxic T cells to eradicate tumors.

    “Remarkably, many of these patients are highly responsive to checkpoint blockade treatment (Diaz and Le, 2015; Le et al., 2017; Le et al., 2015) where the tumor infiltrating CD8+ cytotoxic T cells can be reactivated by anti-PD1 antagonists to effectively eradicate tumors.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Diaz and Le, 2015 source

      Not checked in the free run.

    • cites Le et al., 2017

      Not checked in the free run.

    • cites Le et al., 2015

      Not checked in the free run.

67 of 67

  • The paper relies on this without support.

    IL-17 is the signature cytokine of a distinct CD4+ T helper subset, Th17 cells, which express RORγt and are activated by IL-23.

    “IL-17 is the signature cytokine of a distinct CD4+ T helper subset, T helper 17 (Th17) cells, which are characterized by expression of the “master” transcription factor RORγt and activated by the IL-12-family cytokine, IL-23.”

  • The paper relies on this without support.

    Findings from mouse models of IL-17 biology are informative about human IL-17 biology and disease.

    “Mouse models indicate that IL-17B signaling through IL-17RB promotes survival, proliferation and migration of cancer cells in mouse models”

  • The paper relies on this without support.

    IL-17A is the most strongly implicated IL-17 family member in human health and disease, justifying the review's focus on it.

    “this review will focus on IL-17A as it has been most strongly implicated in human health and disease.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • IL-17 stimulates neutrophils to eliminate extracellular pathogens.

    “In addition, IL-17 stimulates neutrophils to eliminate extracellular pathogens (McGeachy et al., 2019).”

    From Iron in infection and immunity (2020) · cites this paper as McGeachy et al., 2019

    In “IL-17A functions: Barrier surface protection and repair” (page unavailable), the paper says IL-17 induces chemokines that attract neutrophils and that IL-17 responses defend against extracellular fungal and bacterial pathogens. It describes IL-17 as signaling predominantly in non-hematopoietic cells, rather than directly stimulating neutrophils to eliminate pathogens. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
McGeachy, M. J., Cua, D. J., & Gaffen, S. L.
Affiliations
  • University of Pittsburgh (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
  • McGeachy, Mandy J.
  • Cua, Daniel J.
  • Gaffen, Sarah L.
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2019-04
Volume
50
Issue
4
Pages
892-906
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2019.03.021
PMC
PMC6474359
OpenAlex
W2939946042
Semantic Scholar
ac9595c105d61927109ca0a3aaf531e8f062ad1c
Cited by
1,443
References
198
Citations by year
2026: 180 · 2025: 239 · 2024: 266 · 2023: 196 · 2022: 247 · 2021: 165 · 2020: 122 · 2019: 28
FWCI
12.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (AI110822, DE0225500, AI107825)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
IL-17 family, IL-17A, inflammatory cytokines, autoimmune disease, cancer, IL-17 inhibition, infection, injury response, physiological stress
MeSH terms
Animals, Autoimmune Diseases, Brain, Gene Expression Regulation, T-Lymphocytes, Helper-Inducer, Humans, Infections, Inflammation, Neoplasms, Stress, Physiological, Wounds and Injuries, Signal Transduction, Cytokines, RNA-Binding Proteins, Interleukin-17, Mice, Receptors, Interleukin-17, Molecular Targeted Therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review