The focus of this project is to define factors and signal transduction pathways involved in the modulation of human monocyte functions that may contribute to the immunopathology associated with various disease states. Since cytokines are known to be intimately involved in various disease states, we examined individual cytokines as well as combinations of certain cytokines (TNF-alpha, GM-CSF, and IL-1beta) for their effect on the production of monocyte matrix metalloproteinases (MMPs) which are capable of degrading all the connective tissue components. We have shown that certain members of the MMP family can be differentially regulated by these cytokines depending on whether the monocyte is exposed to individual or certain combinations of cytokines. Moreover, the differential effect of these cytokines in the induction of interstitial collagenase is due to the increase in phospholipase activity and the subsequent generation of PGE2. This is in contrast to the enhancement of gelatinase B by individual cytokines which is independent of phospholipase activity and PGE2. Cytokines were also shown to be involved in the induction of monocyte gelatinase B by HIV-Tat. Antibodies against TNF-alpha or IL- 1beta when added to monocyte cultures exposed to HIV-Tat significantly inhibited the induction of gelatinase B. Studies on the early events leading to MMP production by monocytes, using LPS as the stimulant, demonstrated that tyrosine kinase(s) phosphorylate MAP kinases which in turn phosphorylate cytosolic PLA2 (cPLA2) resulting in the release of arachidonic acid and the subsequent generation of PGE2 required for the induction of MMP-1. Utilization of specific inhibitors revealed that while both p38 and p44/42 MAP kinases have a role in the phosphorylation of cPLA2, p38 is the major MAP kinase involved in phosphorylation of cPLA2
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