This study was initiated to assess the role of endogenous interferon on monocyte/macrophage differentiation and activation for host defense functions. Initial observations indicated that bacterial lipopolysaccharide (LPS), a potent monocyte/macrophage activating stimulus, failed to elicit interferon (IFN) production by freshly isolated human monocytes, despite the fact that other monocyte-derived cytokines (tumor necrosis factor, TNF; interleukin-1, IL-1) are produced upon LPS stimulation. However, culture of monocytes in the presence of either interferon-gamma (IFN-gamma) or granulocyte-macrophage colony stimulating factor (GM-CSF) induces the capacity for LPS induction of IFN. TNF and IL-1 are differentially regulated under these conditions, suggesting independent regulation of all of these LPS-induced monokines. Neutralization studies indicate that the IFN produced in response to LPS is primarily of the alpha subtype. Northern analysis, using an IFN-alpha2 cDNA probe, demonstrated that induction by LPS is regulated at the steady- state mRNA level. Current efforts are directed toward defining the molecular mechanism of the priming effects of IFN-~ and GM-CSF, with emphasis on control of transcription and mRNA stability for IFN genes. Preliminary studies have yielded interesting results with regard to regulation of genes encoding nuclear factors putatively involved in IFN gene transcription. Dr. Hayes is also involved in regulatory duties which include review of investigational new drug applications for cytokines with emphasis on interferons.
