関節リウマチとサイトカイン
現在まで知られているを事実を整合性の形で整理すれば、おもに滑膜の何らかの内的外的ストレスによって抗原性が変化して、もともと存在する免疫異常のあるなしに関わらず炎症が起動されるのがその本体と考えられる。その際、悪性なサイトカインスト-ムが緩徐に進行している。
The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone.
Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA
recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role.
Representative cytokines, signal transduction pathways, and their pathogenic roles in rheumatoid arthritis.
| Cytokine-Receptor- Major Signaling Molecules | Proposed Roles in Rheumatoid Arthritis | Clinical Application |
|---|---|---|
| TNF-TNFR 1/2- NF-kB, MAPKs, PI3K | Osteoclastogenesis, TNFR1; Treg inhibition, Proinflammatory cytokine production TNFR2; Treg activation Epigenomic modification (acetylation/methylation) memTNF; protective against arthritis | Widely used |
| IL-6-IL-6R- gp130, JAK1/ 2, Tyk2, STAT1/3, PI3K, SHP-2, ERK | Osteoclastogenesis Proinflammatory cytokine production Autoantibody production Th17 differentiation, Treg inhibition | Widely used (anti-receptor antibody) |
| IL-33-ST2- IL-1-RacP, MyD88, IRAKs, TRAF6, NF-kB, MAPKs, AP1 | Proinflammatory cytokine production Activation of mast cells, Tregs, Th2, and ILC2 | Unreported |
| IL-1β- IL-1R, MyD88, IRAKs, TRAF6, NF-kB MAPKs, AP1 | Inflammation Th17 differentiation, Treg inhibition | Modest or negative |
| IL-18-IL-18Rα/18Rβ MyD88, IRAKs, NF-kB IL-18–IL-18BP | Inflammation Neutralization | Unreported |
| IL-23–IL-12Rβ1/IL-23R- Tyk2, JAK2, STAT3/4 | Activation of Th17, NKT, and ILC3 cells Cytokine production (IL-17, TNF-α, GM-CSF) | Did not meet primary endpoint |
| IL-17–IL-17R ACT1, TRAF6, NF-kB, MAPKs | Proinflammatory cytokine production Osteoclastogenesis Activation of synovial fibroblasts, macrophages | Did not meet primary endpoint |
| IL-7–IL-7R JAK1/3, STAT3/5, PI3K, AKT | Differentiation, expansion of Th17 cells Treg differentiation Osteoclastogenesis | Unreported |
| IL-21 JAK1/3, STAT1/3/5 | Autocrine amplification of Th17 cells Th17 differentiation, Treg inhibition | Phase I/IIa |
| GM-CSF-GM-CSFR- JAK2, STAT3/5 | Macrophage activation Proinflammatory cytokine production | Phase III |
| IL-2–IL-2R- JAK1/2/3, STAT3/5, SHC-1, ERK | Late phase: arthritogenic Activation of ILC2, NK cells, Th17 cells, IL-33 production Early phase: Anti-arthritogenic via IFN-γ Low dose IL-2 Treg activation | Phase I/IIa |
Abbreviations: TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; memTNF, membrane TNF; JAK, Janus kinase; Tyk2, tyrosine kinase 2; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol-3 kinase; SHP-2, Src homology region 2 domain-containing phosphatase 2; ERK, extracellular signal regulated kinase; Th, T helper; Treg, T regulatory; IL, interleukin; IL-1-RacP, IL-1 receptor accessory protein; MyD88, myeloid differentiation factor 88; IRAKs, interleukin-1 receptor associated kinases; TRAF6, tumor necrosis factor receptor-associated factor 6; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; AP1, activator protein 1; ILC2, group 2 innate lymphoid cells; NKT, natural killer T cell; ACT1, nuclear factor activator 1; GM-CSF, granulocyte macrophage colony-stimulating factor; SHC-1, Src homology domain-containing transforming protein 1; IFN-γ, interferon-gamma.
関節リウマチ、関節リウマチ、関節リウチ、山口、山口、山口、山口市、山口県
Cytokine Networks in the Pathogenesis of Rheumatoid Arthritisyoriより
The JAK/STAT signaling pathway appears to be related to bone homeostasis. JAK protein associated with the receptor after formation of the ligand–receptor complex is activated by transphosphorylation. JAK activation induces the phosphorylation of tyrosine on a cytoplasmic tail subunit of the receptor at docking sites for STAT proteins. The STAT proteins then undergo phosphorylation and dimerization, and the dimer translocates into the nucleus, where it binds to DNA and activates the transcription of targeted genes that affect cell behavior. SOCS provides negative feedback to the receptor and prevents continuous signaling. JAK1 and STAT3 signaling is mediated by IL-6 family cytokines, which bind to the gp130 IL-6 receptor subunit and are indispensable for normal skeletal development in mice and humans [138]. IL-6 family cytokines such as IL-6, IL-11, oncostatin M (OSM), cardiotropin-1 (CT-1), and leukemia inhibitory factor (LIF) stimulate activation and production of osteoclast via osteoblast lineage cells [138]. They also stimulate bone formation given that LIF increases trabecular bone mass in vivo and that LIF, IL-6, OSM, and IL-11 act directly on osteoblasts in vitro [138]. G-CSF also stimulates bone formation [139]. The JAK1/STAT3/SOCS3 pathway is activated by these cytokines and promotes both osteoblast and osteoclast formation [139,140]. Tofacitinib (a JAK1/JAK3 inhibitor) dose-dependently reduces RANKL expression in cultured T cells [141]. In a rat adjuvant-induced arthritis model, tofacitinib has been reported to increase bone cortical and trabecular hardness, but it does not reverse the effects of arthritis on cortical and trabecular bone structure [142].
2024年7月14日 | カテゴリー：関節リウマチ リウマチ外来 |
