Influence of Janus Kinase Inhibition on Interleukin 6-mediated Induction of Acute-phase Serum Amyloid A in Rheumatoid Synovium

Abstract

Our data indicated that CP690,550 blocked IL-6-induced JAK2/STAT3 activation, as well as the induction of A-SAA. Inhibition of IL-6-mediated proinflammatory signaling pathways by CP690,550 may represent a new antiinflammatory therapeutic strategy for RA and AA amyloidosis.

Fetuin‐A, serum amyloid A and tumor necrosis factor alpha levels in periodontal health and disease

“…To evaluate the relationship between fetuin‐A and inflammatory markers, we examined the correlations between fetuin‐A, TNF‐ α , and SAA. As previously mentioned, TNF‐ α is an established inflammatory mediator in PD pathogenesis and the production of SAA, one of the most studied biomarkers in various systemic diseases, is stimulated by proinflammatory cytokines such as IL‐6, IL‐1, TNF, IFN‐ γ , and transforming growth factor‐ β (TGF‐ β ) (Page, ; Van Dyke et al , ; Migita et al , ). The results demonstrated that SAA and fetuin‐A are negatively correlated.…”

“…SAA is released in response to inflammation or infection. Production of SAA is stimulated by proinflammatory cytokines such as IL-6, IL-1, TNF, IFN-c, and transforming growth factor-b (TGF-b) (Migita et al, 2011;Nakamura, 2011). SAA may play an important, pathogenic role in the proinflammatory process of RA (Connolly et al, 2012).…”

The acute‐phase mediator serum amyloid A is associated with symptoms of depression and fatigue

“…One of the possible mechanisms could be the observed decrease in circulating SAA levels . Cell culture study using rheumatoid synoviocytes have found that tofacitinib is able to abrogate SAA mRNA expression by preventing JAK‐2/STAT‐3 activation . Another cell culture study has found that pharmacological treatment of human carotid artery endothelial cells with inhibitors of known SAA receptors—FPRL1, RAGE, and TLR2/4—to variable extent prevented SAA‐induced gene expression of several proinflammatory mediators, for example, nuclear factor κ B (NFκB) and TNF .…”

AA Amyloidosis: Mount Sinai Experience, 1997–2012

“…Certain IL‐6 polymorphisms are known to increase IL‐6 production41 and to increase the risk of developing RA in Europeans42; it is possible those same polymorphisms might increase the risk of developing AA amyloidosis. Additional trials are needed to subtype patients with AA amyloidosis as to responsiveness to different biologic agents, to test orally active agents (eg, caspase inhibitors for inflammasome disorders and transcription factor [eg, Janus kinase] inhibitors capable of inhibiting the production of multiple proinflammatory cytokines),43 and to study the effect of SAA messenger RNA inhibition and reductions in the level of the precursor protein 44 Though interleukin‐1β, interleukin‐6, and tumor necrosis factor‐α each stimulate the production of serum amyloid A protein, only interleukin‐6 was consistently elevated in our patients.…”