REGULATION OF M-CSF AND ET-1 PRODUCTION IN HUMAN MONOCYTES

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M-CSF stimulates the survival and differentiation of mononuclear phagocytic cells and can enhance their effector functions. We have foundd that M-CSF production can be transcriptionally induced by cell-to-cell contact (i.e., CD45), augmented by pro-inflammatory cytokines ( i.e., IL-1), and downregulated by anti-inflammatory cytokines (i.e., IL-4 , IL-10 and IL-13). Our finding that MO infection with replication competent HIV -1 results in M-CSF production indicates that M-CSF may contribute to MOs functioning as a viral reservoir for HIV in vivo. Understanding the regulation of M-CSF production by cytokines such as IL-2, which are used therapeutically in AIDS, may help determine parameters that influence HIV replication. Knowledge of the regulation of M-CSF and cytokines such as ET-1, which influences localization of HIV- infected MO in the body during HIV infection, may be important in controlling HIV disease. In this regard, we find that IFN-g, a cytokine active in immune responses, is also a potent regulator of ET-1 gene expression. In as much as AIDS is characterized by a general dysregulation of cytokine production, knowledge of the mechanisms involved in the production and regulation of a number of cytokines may prove to be essential for treating HIV disease. This aspect of the work ongoing in my laboratory is directed at studying the mechanisms involved in the regulation of monocyte expression of 2 specific genes implicated in HIV disease, M-CSF and ET-1. Our results could ultimately lead to new therapeutic approaches directed at regulating monocyte function in specific diseases and controlling the expression of HIV in human monocytes. This research will assist in understanding the rationale and anticipated outcomes of proposed therapies, and determining potential antagonists that could be considered for clinical trials should inhibition of M-CSF or ET-1 production be warranted.