Cellular proliferation in eukaryotic cells is associated with a highly organized sequence of events involving expression of growth-related genes. The growth regulatory cytokines such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin-like growth factor (IGF-I) are thought to be responsible for initiating proliferation of fibroblasts and other connective tissue cells. The immunomodulatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), are also known to modulate the growth response in nonimmune cells and regulate cellular metabolism by inducing expression of genes encoding biologically active molecules. While TGF-beta can induce anchorage-independent growth of nonneoplastic cells, it inhibits the proliferation of most normal cell types. Several of the cytokines that stimulate fibroblast proliferation may inhibit the growth of other cell types. Recent studies have also begun to assign specific roles to different cytokines in embryonic development and cellular differentiation. The growth response to some cytokines may be dependent upon the induction of other cytokines that then directly stimulate proliferation. Some cytokines may also modulate the responses induced by other cytokines by regulating receptor expression and other cellular events. Binding of cytokines to their specific membrane-associated receptors results in activation of signal transduction pathways, many of which involve phosphorylation of specific intercellular proteins. The final biological response is dependent ultimately on the induction and activation of trans-acting factors that regulate transcription by interacting with cis-acting DNA sequences in the target genes. Since many of these signaling and transcriptional events are common to distinct cytokines, many of which have different effects on proliferation in the same cell types, it is not clear how specificity is achieved in regulating the different biological responses.
