The objective of this research program is to define the molecular mechanisms that regulate cytokine expression in monocytes. TGF-beta is a multifunctional peptide which has been implicated as an important immunoregulatory molecule. Upon brief exposure to TGF-beta, monocytes are rapidly induced to express a variety of growth factors, each of which can further amplify inflammatory events by promoting angiogenesis and fibrosis. Prolonged exposure to TGF-beta influences the responsiveness of monocytes to secondary stimuli such as lipopolysaccharide (LPS), interferon-gamma, and interleukin-1. Pretreatment with TGF-beta for 24-48 hr results in enhanced TNF-alpha mRNA levels within 30 min after exposure to LPS as compared to untreated cells. This increase is reflected at the protein level within 3 hr, after which time the TNF levels return to the baseline LPS response or less. Similar pretreatment with TGF-beta also enhances the LPS-induced transcription and translation of IL-1 and GM-CSF, as well as several immediate early genes, including jun and fos. While LPS alone induces the expression of a variety of monokines, exposure to TGF-beta appears to prime the cells to the effects of LPS, influencing the kinetics of the secondary response. These studies suggest that TGF-beta plays an important role in the later phases of the inflammatory response and the interaction between these primed cells and inflammatory cytokines may contribute to chronic inflammation.
