Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Aug 13:18:10953-10967.
doi: 10.2147/JIR.S530754. eCollection 2025.

Role of Interleukin-6 in Rheumatoid Arthritis-Associated Interstitial Lung Disease: Focus on the JAK/STAT Pathway and Macrophage Polarization

Zhiping Yu #  1   2 , Ji Liu #  1 , Letian Chen #  2 , Junping Xie  1
Affiliations
Review

Role of Interleukin-6 in Rheumatoid Arthritis-Associated Interstitial Lung Disease: Focus on the JAK/STAT Pathway and Macrophage Polarization

Zhiping Yu et al. J Inflamm Res. .

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic synovitis and extra-articular manifestations (EAMs), with interstitial lung disease (ILD) being a leading cause of mortality. Interleukin-6 (IL-6), a pivotal cytokine in RA pathogenesis, drives both articular and pulmonary inflammation through its involvement in immune dysregulation and fibrotic processes. This review elucidates the molecular mechanisms by which IL-6 contributes to rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression, particularly via the Janus kinases (JAK)/signal transducers and activators of transcription (STAT) signaling pathway and macrophage polarization. Additionally, we objectively evaluate current and emerging therapeutic strategies targeting IL-6 and downstream pathways.

Keywords: IL-6; JAK/STAT signaling; RA-ILD; macrophage polarization; targeted therapy.

PubMed Disclaimer

Conflict of interest statement

All the authors of this manuscript report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
IL-6 plays a pivotal role in initiating and sustaining inflammation in RA. Antigen-antibody complexes trigger the accumulation of immune cells, including macrophages and B cells, as well as synovial fibroblasts, within the joints, leading to the release of IL-6. Created in BioRender. Yu, Z. (2025) https://BioRender.com/69itnxw.
Figure 2
Figure 2
The IL-6 signaling cascade: the JAK/STAT pathway activated through the IL-6/sIL-6R/gp130 complex, driving transcriptional regulation of pro-fibrotic genes. Created in BioRender. Yu, Z. (2025) https://BioRender.com/z25hgmg.
Figure 3
Figure 3
IL-6 may promote fibroblast proliferation and transformation through a non-fibroblast paracrine pathway. TGF-β binds to its receptor and regulates gene transcription via the Smad-dependent pathway, inducing non-fibroblasts to secrete IL-6, which stimulates fibroblast proliferation and their transformation into myofibroblasts. The dashed line indicates that FMT is enhanced through paracrine signaling. Created in BioRender. Yu, Z. (2025) https://BioRender.com/irwalcz.
Figure 4
Figure 4
Differential functions of M1/M2 macrophage polarization in the repair of normal inflammatory injury. Role of M1/M2 polarization imbalance in pulmonary fibrosis. M2 macrophages induce IL-6/sIL-6 complex formation. IL-6 promotes hyperpolarization of M2 macrophages. Created in BioRender. Yu, Z. (2025) https://BioRender.com/xmv8jpk and Created in BioRender. Yu, Z. (2025) https://BioRender.com/f5oerjc.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. D’Orazio A, Cirillo AL, Greco G, et al. Pathogenesis of rheumatoid arthritis: one year in review 2024. Clin Exp Rheumatol. 2024;42(9):1707–1713. doi: 10.55563/clinexprheumatol/0307ed - DOI - PubMed
    1. Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management. Eur Respir Rev. 2021;30(160):210011. doi: 10.1183/16000617.0011-2021 - DOI - PMC - PubMed
    1. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheumatic Dis. 2003;62(8):722–727. doi: 10.1136/ard.62.8.722 - DOI - PMC - PubMed
    1. Zhang Y, Li H, Wu N, Dong X, Zheng Y. Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease. Clin Rheumatol. 2017;36(4):817–823. doi: 10.1007/s10067-017-3561-5 - DOI - PubMed
    1. Kim Y, Yang HI, Kim KS. Etiology and pathogenesis of rheumatoid arthritis-interstitial lung disease. Int J Mol Sci. 2023;24(19):14509. doi: 10.3390/ijms241914509 - DOI - PMC - PubMed

LinkOut - more resources