Chronic and acute inflammatory conditions determine MEK1 or MEK2 usage as regulators of IL-1β and sIL-1ra expression (117.18)

Abstract

Abstract Deregulation of the production of IL-1β and its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra), plays an important role in chronic inflammatory diseases such as multiple sclerosis. Relevant to this condition direct cellular contact with stimulated T cells potently triggers cytokine production in human monocytes. In this study we investigated the implication of MEK1 and MEK2 in the control of IL-1β and sIL-1Ra production by human monocytes upon two different stimuli: (i) soluble extracts of plasma membranes from stimulated T cells (CEsHUT), mimicking cellular contact with T cells that is relevant to chronic/sterile inflammation; and (ii) LPS that is relevant to acute/infectious inflammation. By using MEK1/2 (U0126) and MEK1 (PD98059) inhibitors and siRNA specific to MEK1 and MEK2 we demonstrate that MEK1 and MEK2 are differentially involved in the induction of IL-1β production upon chronic/sterile and acute/infectious inflammatory conditions, MEK1 being dispensable to IL-1β induction in monocytes activated by LPS but required in CEsHUT-activated monocytes. Together with the fact that immunomodulatory treatments of multiple sclerosis - IFNβ and glatiramer acetate - are using MEK2 to induce sIL-1Ra production in human monocytes, MEK1 represents a potential therapeutic target which could participate in the restoration of IL-1β/sIL-1Ra balance in chronic/sterile inflammation without affecting normal response to infectious agents.