Transforming growth factor beta(1) rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages

Cell death and cell survival are central components of normal development a nd pathologic states. Transforming growth factor beta(1) (TGF-beta(1)) is a pleiotropic cytokine that regulates both cell growth and cell death. To be tter understand the molecular mechanisms that control cell death or surviva l, we investigated the role of TGF-beta(1) in the apoptotic process by domi nant-negative inhibition of both TGF-beta(1) and mitogen-activated protein kinase (MAPK) signaling pathways. Murine macrophages (RAW 264.7) undergo ap optosis following serum deprivation, as determined by DNA laddering assay. However, apoptosis is prevented in serum-deprived macrophages by the presen ce of exogenous TGF-beta(1). Using stably transfected RAW 264.7 cells with the kinase-deleted dominant-negative mutant of T beta R-II (T beta R-IIM) c DNA, we demonstrate that this protective effect by TGF-beta(1) is completel y abrogated. To determine the downstream signaling pathways, we examined TG F-beta(1) effects on the MAPK pathway. We show that TGF-beta(1) induces the extracellular signal-regulated kinase (ERK) activity in a time-dependent m anner up to 4 h after stimulation. Furthermore, TGF-beta(1) does not rescue serum deprivation-induced apoptosis in RAW 264.7 cells transfected with a dominant-negative mutant MAPK (ERK2) cDNA or in wild type RAW 264.7 cells i n the presence of the MAPK kinase (MEK1) inhibitor. Taken together, our dat a demonstrate for the first time that TGF-beta(1) is an inhibitor of apopto sis in cultured macrophages and may serve as a cell survival factor via T b eta R-II-mediated signaling and downstream intracellular MAPK signaling pat hway.