Tumor necrosis factor (TNF) plays important roles in host resistance to cancer and infections, but this cytokine also acts as a key mediator of pathologies in autoimmunity, septic shock and cachexia. The long-term goal of our studies is to explain the molecular mechanisms whereby TNF produces its important biological actions. Elucidation of intracellular signaling pathways is essential for understanding how TNF and other related cytokines produce the multitude of their actions as well as for the design of methods that would inhibit their undesirable effects in the intact organism. In this application we propose to determine the roles played by members of the large family of mitogen activated protein (MAP) kinases in TNF actions. The hypothesis to be examined is that the ERK, JNK/SAPK and p38 MAP kinases are important mediators of TNF actions and that each of these MAP kinase subfamilies plays specific roles in the different cellular functions activated by TNF. The first specific aim is to determine the roles of the major MAP kinase subfamilies in the activation of gene expression by TNF. Toward this end we shall analyze the involvement of MAP kinases in the TNF-induced activation of the IL-6 and IL-8 genes in which the roles of specific transcription factors (especially NF-kappaB and NF-IL6) have been extensively documented. We shall also determine the roles of MAP kinases on the activation of genes responsive to the AP-1 and IRF-1 transcription factors. The second specific aim is to determine the mechanism whereby the p38 kinase mediates inhibition of TNF-induced NF-kappaB activation. We shall determine whether p38 activation alone is sufficient to inhibit TNF- induced I-kappaBalpha phosphorylation and degradation, and which of the intracellular signaling proteins known to mediate NF-kappaB activation by the p55 TNF receptor is the target of the inhibitory action mediated by p38. These studies will help to understand signaling pathways activated by TNF and will contribute to the design of methods for the inhibition of undesirable side effects of TNF in pathological conditions.
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