INHIBITION OF MAP KINASE KINASE PREVENTS CYTOKINE AND PROSTAGLANDIN E-2 PRODUCTION IN LIPOPOLYSACCHARIDE-STIMULATED MONOCYTES

Activation of the extracellular signal-regulated kinase (ERK) pathway has been shown to occur in monocytes following stimulation with LPS. H owever, the importance of this event for monocyte function is not clea r. To address this issue, we used the novel MAP/ERK kinase (MEK) inhib itor, U0126, Stimulation of monocytes with LPS resulted in activation of the mitogen-activated protein kinase (MAPK) family members ERK, Jun NH2-terminal kinase (JNK), and p38. Treatment of monocytes with LPS i n the presence of U0126 blocked the activation of ERK1 and ERK2. Howev er, the activation of Jun NH2-terminal kinase and p38 family members w as not affected by the compound, confirming the selectivity of U0126. To examine the effects of MEK inhibition on monocyte function, we meas ured production of the cytokines IL-1, IL-8, and TNF, as well as PGE. Monocytes treated with LPS in the presence of U0126 failed to release IL-1, IL-8, TNF, or PGE. The failure to secrete IL-1 and TNF was due t o decreased levels of mRNA. These results demonstrate that activation of MEK/ERK is critical for cytokine and PGE, production by monocytes i n response to LPS.