MIF modulates p38/ERK phosphorylation via MKP-1 induction in sarcoidosis

Macrophage migration inhibitory factor (MIF) is a versatile cytokine that influences a variety of cellular processes important for immune regulation and tissue homeostasis. Sarcoidosis is a granulomatous disease characterized by extensive local inflammation and increased T helper cell mediated cytokines. We have shown that MIF has a modulatory role in cytokine networks in sarcoidosis. We investigated the effect of exogenous MIF on sarcoidosis alveolar macrophages (AMs), CD14+ monocytes and peripheral blood mononuclear cells (PBMCs). Our results showed that MIF negatively regulates the increased MAPKs (pp38 and pERK1/2) activation by inducing Mitogen-activated protein kinase phosphatase (MKP)-1. We found that MIF decreased IL-6 and IL-1β production, increased the percentage of regulatory T-cells (Tregs), and induced IL-1R antagonist (IL-1RA) and IL-10 production. Thus, the results of our study suggest that exogenous MIF modulates MAPK activation by inducing MKP-1and Tregs as well as IL-10 and IL-1RA, and hence plays a modulatory role in immune activation in sarcoidosis. [Display omitted] •Sarcoidosis CD4 and CD8 T-cells exhibit lower intracellular MIF•Sarcoidosis is associated with dysregulation of MAP-kinase (p38) activation MKP-1•Exogenous MIF upregulated MKP-1 and modulates p38 and ERK1/2 phosphorylation•Exogenous MIF decreased IL-6 and IL-1® production and induced IL-1RA and Tregs