The IL-17 Family of Cytokines in Health and Disease

In the paper

“In mice, segmented filamentous bacteria (SFB) form direct physical contact with mouse intestinal epithelial cells and thereby promote intestinal IL-17 signature genes”

What the sources say

• Partly supported

  The Introduction and Results report that SFB adhere tightly to mouse intestinal epithelial cells. The Results section on the gut immune response reports increased expression of Th17-associated genes, including Il17, after SFB colonization. The paper does not establish that physical contact itself causes that increase, as the word “thereby” implies. (LLM, conf=0.85)

  cites Ivanov et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“present in species as early as jawless fish as well as Mollusca and sea urchins”

What the sources say

• Not checked yetcites Buckley et al., 2017 source
• Not checked yetcites Han et al., 2015 source
• Not checked yetcites Novatchkova et al., 2003 source

In the paper

“this cytokine was elevated in human inflammatory or autoimmune diseases and was expressed in a non-canonical T helper cell population”

What the sources say

• Not checked yetcites Albanesi et al., 1999 source
• Not checked yetcites Antonysamy et al., 1999 source
• Not checked yetcites Infante-Duarte et al., 2000 source

In the paper

“The so-called “IL-23-IL-17 axis” was found to function as a critical driver of autoimmune disease”

What the sources say

• Not checked yetcites Duerr et al., 2006 source
• Not checked yetcites Harrington et al., 2005 source
• Not checked yetcites Langrish et al., 2005 source

In the paper

“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”

What the sources say

• Not checked yetcites Cua and Tato, 2010

In the paper

“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”

What the sources say

• Not checked yetcites Liu et al., 2011a
• Not checked yetcites Qian et al., 2007 source
• Not checked yetcites Sonder et al., 2011

In the paper

“IκBζ is implicated in psoriasis both genetically and functionally”

What the sources say

• Not checked yetcites Johansen et al., 2015 source
• Not checked yetcites Tsoi et al., 2015 source

In the paper

“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”

What the sources say

• Not checked yetcites Gaffen, 2011 source
• Not checked yetcites Yao et al., 1995a

In the paper

“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”

What the sources say

• Not checked yetcites Chiricozzi and Krueger, 2013
• Not checked yetcites Ha et al., 2014
• Not checked yetcites Langowski et al., 2006 source

In the paper

“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”

What the sources say

• Not checked yetcites Wu et al., 2015c

In the paper

“TRAF6 also promotes activation of MAPK/AP1 pathways and the C/EBPβ and δ transcription factors”

What the sources say

• Not checked yetcites Chang et al., 2006 source
• Not checked yetcites Maitra et al., 2007 source
• Not checked yetcites Qian et al., 2007 source

In the paper

“IL-17B was originally found to increase during intestinal inflammation and to promote neutrophil migration upon intraperitoneal administration, suggesting a pro-inflammatory role”

What the sources say

• Not checked yetcites Bie et al., 2017a
• Not checked yetcites Shi et al., 2000 source

In the paper

“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”

What the sources say

• Not checked yetcites Karlsen et al., 2010 source
• Not checked yetcites Ruddy et al., 2004 source
• Not checked yetcites Tohyama et al., 2018 source

In the paper

“IL-17 was suggested to regulate NF-κB and CCL20 through CARMA2, encoded by CARD14”

What the sources say

• Not checked yetcites Tsoi et al., 2012 source
• Not checked yetcites Wang et al., 2018 source

In the paper

“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”

What the sources say

• Not checked yetcites Conti and Gaffen, 2015
• Not checked yetcites Li et al., 2017

In the paper

“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.”

In the paper

“IL-17C promotes anti-microbial protective responses and barrier maintenance in skin and intestine”

What the sources say

• Not checked yetcites Ramirez-Carrozzi et al., 2011 source
• Not checked yetcites Song et al., 2011 source

In the paper

“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”

What the sources say

• Not checked yetcites Bornstein et al., 2018 source
• Not checked yetcites Miller et al., 2018 source

In the paper

“These results indicate that IL-25 is a “barrier surface” cytokine and its production is largely regulated by environmental cues.”

In the paper

“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”

What the sources say

• Not checked yetcites Puel et al., 2011b

In the paper

“It is expressed in a wide variety of healthy tissues, and has been found to increase in tumors and during viral infection”

What the sources say

• Not checked yetcites Saddawi-Konefka et al., 2016 source
• Not checked yetcites Seelige et al., 2017 source
• Not checked yetcites Starnes et al., 2002 source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites Owyang et al., 2006 source

In the paper

“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”

What the sources say

• Not checked yetcites Chang and Dong, 2007
• Not checked yetcites Wright et al., 2007 source

In the paper

“IL-25 treatment elevated production of IL-13 and suppressed expression of IL-1, IL-6, and IL-23 by activated dendritic cells”

What the sources say

• Not checked yetcites Kleinschek et al., 2007 source

In the paper

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

What the sources say

• Not checked yetcites Akimzhanov et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hueber et al., 2012 source
• Not checked yetcites Targan et al., 2016 source

In the paper

“IL-17 induces IL-6 and G-CSF, cytokines that promote myeloid-driven innate inflammation”

What the sources say

• Not checked yetcites Gaffen et al., 2014 source

In the paper

“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.”

What the sources say

• Not checked yetcites Kleinschek et al., 2009 source

In the paper

“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”

What the sources say

• Not checked yetcites Lee et al., 2015 source
• Not checked yetcites Maxwell et al., 2015 source
• Not checked yetcites Whibley and Gaffen, 2015

In the paper

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

In the paper

“this pro-proliferative role likely contributes to the pathogenic effects of IL-17 in psoriasis, as well as potentially in skin cancer”

What the sources say

• Not checked yetcites Chen et al., 2019 source
• Not checked yetcites Lai et al., 2012 source
• Not checked yetcites Langowski et al., 2006 source

In the paper

“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”

What the sources say

• Not checked yetcites Dutzan et al., 2017b

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites Yu et al., 2007

In the paper

“IL-17 promotes glomerulonephritis following immune complex deposition in the kidney, and is thus thought to contribute to lupus renal disease”

What the sources say

• Not checked yetcites Pisitkun et al., 2012 source
• Not checked yetcites Ramani et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Choi et al., 2016 source
• Not checked yetcites Kim et al., 2017 source

In the paper

“Th17 cells exacerbated depression-like symptoms in mice, and infiltrated the pre-frontal cortex and particularly hippocampus in depressed mice compared to controls”

What the sources say

• Not checked yetcites Beurel et al., 2013 source
• Not checked yetcites Beurel and Lowell, 2018 source

In the paper

“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”

What the sources say

• Not checked yetcites Scher et al., 2013 source
• Not checked yetcites Maeda et al., 2016 source
• Not checked yetcites Wu et al., 2010

In the paper

“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”

What the sources say

• Not checked yetcites Dutzan et al., 2017a

In the paper

“IL-17 blockade was effective in psoriatic arthritis (PsA) (McInnes et al., 2014; Mease and McInnes, 2016) as well as ankylosing spondylitis (AS)”

What the sources say

• Not checked yetcites McInnes et al., 2014 source
• Not checked yetcites Mease and McInnes, 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Siffrin et al., 2010 source
• Not checked yetcites Kang et al., 2013 source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Ramani et al., 2016 source
• Not checked yetcites Ramani et al., 2018b

In the paper

“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.”

In the paper

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

In the paper

“traumatic or ischemic brain injury patients frequently develop dysbiosis during hospitalization, which could alter immune responses in the inflamed brain”

What the sources say

• Not checked yetcites Simon et al., 2017 source

In the paper

“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”

What the sources say

• Not checked yetcites Ramani et al., 2018a

In the paper

“In the healthy state, IL-17 directly influences the metabolic function of adipocytes, increasing expression of thermogenic enzymes and sensitivity to catecholamine”

What the sources say

• Not checked yetcites Kohlgruber et al., 2018 source

In the paper

“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”

What the sources say

• Not checked yetcites Ahmed and Gaffen, 2013
• Not checked yetcites Goswami et al., 2009 source
• Not checked yetcites Zuniga et al., 2010 source

In the paper

“Phase II trials of secukinumab were reported to be successful in MS, but larger trials have yet to be initiated”

What the sources say

• Not checked yetcites Patel and Kuchroo, 2015

In the paper

“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).”

What the sources say

• Not checked yetcites Farez et al., 2015 source
• Not checked yetcites Amir et al., 2018 source
• Not checked yetcites Yu et al., 2013

In the paper

“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).”

What the sources say

• Not checked yetcites Kumar et al., 2016 source
• Not checked yetcites Benakis et al., 2016 source

In the paper

“IL-17-deficient mice are susceptible to hypothermia, despite increased total body fat and accumulation of lipid droplets within adipocytes”

What the sources say

• Not checked yetcites Kohlgruber et al., 2018 source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Gelderblom et al., 2012 source
• Not checked yetcites Shichita et al., 2009 source

In the paper

“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”

What the sources say

• Not checked yetcites Mino et al., 2015 source

In the paper

“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”

What the sources say

• Not checked yetcites Amatya et al., 2018 source
• Not checked yetcites Bulek et al., 2011 source
• Not checked yetcites Datta et al., 2010 source

In the paper

“Interestingly, Regnase-1 and Roquins regulate IL-17 production by regulating Th17 differentiation”

What the sources say

• Not checked yetcites Jeltsch et al., 2014 source

In the paper

“that degrades IL-17-induced mRNA transcripts, thus acting as a feedback inhibitor”

What the sources say

• Not checked yetcites Akira, 2013 source
• Not checked yetcites Fu and Blackshear, 2017

In the paper

“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”

In the paper

“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”

What the sources say

• Not checked yetcites Tosolini et al., 2011 source

In the paper

“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)”

What the sources say

• Not checked yetcites Faour et al., 2003 source
• Not checked yetcites Miossec, 2003 source
• Not checked yetcites Ruddy et al., 2004 source

In the paper

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

What the sources say

• Not checked yetcites Jeltsch et al., 2014 source

In the paper

“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.”

In the paper

“Anti-IL-17 was administered and cleared the psoriasis, but unfortunately the cancer progressed”

What the sources say

• Not checked yetcites Esfahani and Miller, 2017

In the paper

“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.”

What the sources say

• Not checked yetcites Diaz and Le, 2015 source
• Not checked yetcites Le et al., 2017
• Not checked yetcites Le et al., 2015