INDUCTION OF CYTOKINE MRNA EXPRESSION IN U937 CELLS BY SALMONELLA TYPHIMURIUM PORINS IS REGULATED BY DIFFERENT PHOSPHORYLATION PATHWAYS.

Lipopolysaccharide (LPS) and porins of Gram-negative outer membranes are the main pathogenic factors implicated in the clinical syndrome of septic shock. The biological activity of porins and LPS are similar, but they occur by different mechanisms. It seems that porins act through different intracellular pathways with respect to LPS. In this study we analyzed the role of several inhibitors of the MEK/ERK signal pathway on the induction of proinflammatory and immunological cytokines in U937 cell line stimulated by Salmonella typhimurium porins and compared it to the cytokine induction after LPS stimulation. We investigated the effects of p38 MAP kinase inhibitor SB-203580, MEK/ERK kinase inhibitor PD-098059 and Raf-1 inhibitor forskolin, and demonstrated that they modulate cytokine mRNA expression in a different manner as a consequence of the use of porins or LPS as stimuli. TNF-alpha and IL-1beta mRNA expression is decreased by PD-098059 after stimulation with LPS but not with porins in differentiated U937 cells. IL-10 mRNA expression is inhibited by SB-203580 and PD-098059 after stimulation with porins in U937 cells. IL-6 and IL-8 mRNA expression is not changed by PD-098059 or SB-203580, after stimulation either with porins or LPS. Furthermore, mRNA expression of the studied cytokines, except for GM-CSF, is not changed using forskolin.