IL-1  and TNF -initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

“…They found that the pro-inflammatory cytokines that are highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and, in turn, induced the expression of cytokines from the IL-6 family. STAT3 activation also induced expression of the receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis [5].…”

“…Up-regulated levels of STAT3 mRNA in mononuclear cells from peripheral blood and synovial fluid, and elevated STAT1 expression in synovial fluid have been observed in active RA [4]. STAT3 has been found to be responsible for joint degradation in RA [5]. The effectiveness of treatment with tocilizumab (which influences STAT3 activation through IL-6) and tofacitinib (a JAK1 and JAK3 inhibitor) constitutes indirect evidence of the influence of JAK/STAT signaling on RA activity [6].…”

IL-4, JAK-STAT signaling, and pain

“…There is evidence that IL-6 and STAT3 activation are the key mediators of both chronic inflammation and joint destruction in rheumatoid arthritis. 40 By inhibiting STAT3 the authors found reduced inflammation and joint destruction in a model of collagen-induced arthritis through a significant reduction in the expression of IL-6 family cytokines and NFκB, indicating pro-inflammatory action of IL-6. The pronociceptive properties of IL-6 became overt in IL-6 knockout mice.…”

Th17 Cells Carrying TCR Recognizing Epidermal Autoantigen Induce Psoriasis-like Skin Inflammation

“…As previously reported (30), rabbit polyclonal anti-phospho-Stat3 (tyr705) (Cell Signaling) was used as the primary Ab and incubated at 4˚C overnight. Goat anti-rabbit IgG conjugated to Alexa Fluor 568 was used as a secondary Ab and incubated at room temperature for 1 h.…”