Deregulation of the production of IL-1 and its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra), plays an important role in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Relevant to the latter conditions direct cellular contact with stimulated T cells potently triggers cytokine production in human monocytes. Identification of signal transduction pathways specific to pathogenic induction of cytokines may lead to new therapeutic approaches. Two different stimuli were compared to investigate the implication of MEK1 and MEK2 in the control of IL-1 and sIL-1Ra production by human monocytes: (i) soluble extracts of plasma membranes from stimulated T cells (CEsHUT), mimicking cellular contact with T cells, i.e., chronic/sterile inflammatory conditions; and (ii) LPS that is relevant to infectious inflammation. The ATP-noncompetitive MEK1/2 (U0126) and MEK1 (PD98059) specific inhibitors diminished the expression (protein and mRNA) of IL-1 in CEsHUT-activated monocytes. In contrast, only the concomitant inhibition of MEK1 and MEK2 inhibited IL-1 production in LPS-activated monocytes, whereas the inhibition of MEK1 only did not affect IL-1 production. In CEsHUT- and LPS-activated monocytes, MEK1 inhibition slightly affected sIL-1Ra production that was significantly inhibited by U0126. These results suggest that MEK1 and MEK2 are differentially involved in the regulation of the IL-1 system upon chronic/sterile and infectious inflammatory conditions. MEK1 which is dispensable to IL-1 production in LPS-activated monocytes represents a potential therapeutic target whose inhibition could participate in the restoration of IL-1/sIL-1Ra balance in chronic/sterile inflammation without affecting regular responses to pathogens.