IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4+ T cells via p-Akt signaling
Bhattacharya, G.; Sengupta, S.; Jha, R.; Shaw, S. K.; Jogdand, G. M.; Barik, P. K.; Padhan, P.; Parida, J. R.; Devadas, S.
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The role of CD4+ T cells specifically, Th17 has been well documented in RA pathogenesis. Here we focus on the critical role of cytokines IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Neutralizing IL-21 or IL- 23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-, IFN-{gamma} and IL- 17 and RANKL expression in RA CD4+ T cells. Our ex vivo human Th17 studies also validated the above findings and we hypothesize a common pathway responsible for regulation of inflammatory cytokines and RANKL expression. Subsequent dissection of the signalling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of augmenting inflammatory cytokines and RANKL production. Altogether, these findings identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher osteoclastogenesis and provide critical targets in their downstream signalling for therapeutic approaches.
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