IL-27 Alleviates Bone Loss in Estrogen Deficient Conditions by Induction of Early Growth Response-2 Gene [Immunology]

Growing understanding of the bone remodeling process suggests that inflammation significantly contributes to the pathogenesis of osteoporosis. T cells and various cytokines contribute majorly to the estrogen deficiency induced bone loss. Recent studies have identified IL-12 cytokine family comprising of pro-inflammatory IL-12 and IL-23 and the anti-inflammatory IL-27 and IL-35 cytokines. IL-27 exerts protective effects in autoimmune diseases like experimental autoimmune encephalomyelitis however; its role in pathogenesis of osteoporosis remains to be determined. In this report, we study the effect of IL-27 supplementation to ovariectomized estrogen deficient mice on various immune and skeletal parameters. IL-27 treatment in ovx mice suppressed Th17 cell differentiation by inhibiting transcription factor RORγt. Supplementation of IL-27 activates Egr-2 to induce IL-10 producing Tr1 cells. IL-27 treatment prevented the loss of trabecular micro architecture and preserved cortical bone parameters. IL-27 also inhibited osteoblast apoptosis through increased Egr-2 expression which induces anti-apoptotic factors like MCL-1. IL-27 suppressed osteoclastogenesis in an Egr-2 dependent manner which up regulates Id2, repressor of RANKL mediated osteoclastogenesis. Additionally, these results were corroborated in female osteoporotic subjects where we found decreased serum IL-27 levels along with reduced Egr-2 expression. Our study forms a strong basis for using humanized IL-27 towards the treatment of postmenopausal osteoporosis.

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