The objectives of this research program are to define the cytokines elaborated by the cells involved in the inflammatory process and in various expression. Transforming growth factor-beta (TGF-beta) induces monocyte chemotaxis and growth factor production, specifically interleukin-1 (IL-1) platelet-derived growth factor (c-sis), tumor necrosis factor-alpha (TNF-alpha), and fibroblast growth factor (FGF), yet blocks the ability of IL-1 to stimulate lymphocyte proliferation. In addition, TGF-beta upregulates expression of TGF-beta mRNA, while lipopolysaccharide (LPS) causes a reduction in the basal level of TGF-beta mRNA. This reduction of TGF-beta message can be reversed in the presence of cycloheximide, suggesting that a regulatory protein may control the expression of the TGF-beta gene. Activated monocytes secrete TGF- beta protein and treatment with anti-TGF-beta antibodies blocks expression IL-1 RNA, suggesting that IL-1 production by activated expression of TGF-beta may contribute to the outcome of an inflammatory lesion by promoting wound healing while limiting tissue damage. Inappropriate expression of cytokines and cell surface antigens may play an important role in disease conditions. Increased levels of IL-1, TNF-beta, and IL-2R mRNAs are seen within 2 to 4 hr after in vitro exposure to HIV-1, suggesting that the virus is acting as an activating agent. Spontaneous and LPS- induced levels of TNF-alpha, IL-1, TGF-beta, and granulocyte- macrophage colony stimulating factor (GM-CSF) RNAs are increased in monocyte cultures where viral replication is rapidly increasing. During this same period, expression of RNAs encoding the cell surface proteins IL-2R, HLA-DR, and T4 is dramatically decreased in HIV-infected monocytes. The modulation of cytokine and cell surface protein expression in HIV-infected monocytes suggest that transactivating elements which regulate HIV expression may also contribute to the activation or inactivation of certain host genes.
