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Cited by 870Cytokine Signaling Pathways and InteractionsRheumatoid Arthritis Research and TherapiesPsoriasis: Treatment and Pathogenesis

Targeting Interleukin-6 Signaling in Clinic

Open access
Kang, Sujin, Tanaka, Toshio, Narazaki, Masashi, Kishimoto, Tadamitsu·2019·Immunity
DOI 10.1016/j.immuni.2019.03.026
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Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.

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  • Clinical trials with JAK/STAT inhibitors are underway for the therapy of cancers and inflammatory diseases.

    “The clinical trials with JAK/STAT inhibitors are underway for the therapy of cancers and inflammatory diseases (Fig. 5) [12, 99].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [12]

  • Both tocilizumab, a monoclonal antibody directed at the interleukin-6 receptor, and siltuximab, which neutralizes interleukin-6 directly, have been shown to be effective in a number of cytokine storm disorders, including HLH, idiopathic multicentric Castleman's disease, and CAR T-cell-induced cytokine storm.

    “Both tocilizumab, a monoclonal antibody directed at the interleukin-6 receptor (interleukin-6R), and siltuximab, which neutralizes interleukin-6 directly, have been shown to be effective in a number of cytokine storm disorders, including HLH, idiopathic multicentric Castleman’s disease, and CAR T-cell–induced cytokine storm.”

    From Cytokine storm (2020) · cites this paper as [38]

  • Interleukin-6 can signal through two main pathways, referred to as classic cis signaling and trans signaling.

    “It can signal through two main pathways, referred to as classic cis signaling and trans signaling.”

    From Cytokine storm (2020) · cites this paper as [38]

  • Activation of cis signaling results in pleiotropic effects on the immune system, which can contribute to cytokine storm.

    “Activation of cis signaling results in pleiotropic effects on the immune system, which can contribute to cytokine storm.”

    From Cytokine storm (2020) · cites this paper as [38]

  • This trans signaling results in systemic hyperinflammation involving secretion of MCP-1, interleukin-8, and additional interleukin-6, as well as increased VEGF and reduced E-cadherin expression on endothelial cells, which contribute to vascular hyperpermeability, leakiness, hypotension, and pulmonary dysfunction.

    “This results in systemic hyperinflammation involving secretion of monocyte chemoattractant protein 1 (MCP-1), interleukin-8, and additional interleukin-6, as well as increased vascular endothelial growth factor (VEGF) and reduced E-cadherin expression on endothelial cells, which contribute to vascular hyperpermeability, leakiness, hypotension, and pulmonary dysfunction.”

    From Cytokine storm (2020) · cites this paper as [38]

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Authors
Kang, S., Tanaka, T., Narazaki, M., & Kishimoto, T.
Affiliations
  • The University of Osaka (JP)
  • Osaka Habikino Medical Center (JP)
Corresponding author
Kishimoto, Tadamitsu
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2019-04
Volume
50
Issue
4
Pages
1007-1023
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2019.03.026
OpenAlex
W2938774134
Cited by
870
References
152
Citations by year
2026: 65 · 2025: 94 · 2024: 117 · 2023: 140 · 2022: 141 · 2021: 160 · 2020: 140 · 2019: 13
FWCI
41.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Astellas Foundation for Research on Metabolic Disorders
  • Kishimoto Foundation
  • Ministry of Education, Culture, Sports, Science and Technology
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
interleukin-6, IL-6 receptor signaling, IL-6 inhibition, rheumatoid arthritis, inflammation, cytokine therapy, treatment resistance
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Interleukin-6 Inhibitors, Animals, Antibodies, Monoclonal, Arthritis, Rheumatoid, Clinical Trials as Topic, Humans, Inflammation, Ribonucleases, Signal Transduction, Interleukin-6, Mice, Knockout, Receptors, Interleukin-6, MAP Kinase Signaling System, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Janus Kinases, Molecular Targeted Therapy

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