Abstract Text: In psoriasis and psoriatic arthritis (PsA) aberrant activation/migration of specific T cell subpopulations (Th17,Th9,MAIT cells) in the skin and joint synovium induce local inflammation and upregulation of cytokines such as IL-9, IL-17A/IL-17F and IL-22 for activation and proliferation of keratinocytes and synovial cells (FLS) which leads to plaque and pannus formation. Among these JAK-1,3 are activated by IL-9 and JAK1/TYK2 by IL-22. There are reports suggesting JAK/STAT signaling system is active in human keratinocytes and in the joint FLS the two key regulatory cells for the disease process of psoriasis and PsA. JAK/STAT signaling system on T cells is well established but its function in keratinocyte and FLS biology and its regulatory role on pannus/plaque formation remains unknown.
Here we hypothesized that IL-9 and IL22 induced JAK/STAT signaling has regulatory role in the inflammatory/proliferative cascades of KC and FLS in psoriasis and PsA. In cultured FLS and KC we observed that compared to the media rIL-22 and rIL-9 induced increased phosphorylation of JAK1/TYK2 and JAK1/JAK3 respectively (p < 0.01). IL9/IL22 also activated STAT3/RORγt. The critical events induced by IL-22 and IL-9 in psoriasis/PsA such as cell proliferation; IL-6, IL-8 and MMP-3 production of KC and FLS were regulated by the respected JAK-STAT kinases associated with IL-22 and IL-9. Further pan-JAK inhibitors and other specific JAK-1 and TYK2 inhibitors could effectively block these effects (p < 0.001). These data provide a novel insight about the role for JAK-STAT signaling in the pathogenesis of psoriatic disease and provide mechanisms of actions of specific JAK inhibitors.
