Transforming growth factor-beta primes macrophages to express inflammatory gene products in response to particulate...

Macrophages maintain an essential role in orchestrating the host inflammatory response by selectively mobilizing portions of their large secretory repertoire in response to phagocytic as well as other stimuli. For example, after exposure to the inflammatory particulate stimulus zymosan (or its derivative beta 1,3-glucan), monocyte/macrophages synthesize and release lysosomal hydrolases, mobilize arachadonic acid, and secrete cytokines such as TNF-alpha and IL-8. However, the mechanisms by which particulate stimuli promote the selective synthesis and release of macrophage-derived inflammatory gene products are unknown. Given the previously reported potential of transforming growth factor-beta (TGF-beta) as an important mediator of the inflammatory response in vivo, we investigated the role of TGF-beta in the regulation of particulate-induced macrophage inflammatory gene expression. We determined that TGF-beta primed macrophages to synthesize lysosomal hydrolases and express platelet-derived growth factor-B mRNA transcripts in response to both submaximal doses of beta 1,3-glucan and the nonspecific phagocytic stimulus latex particles, which by themselves did not induce expression of either inflammatory gene product. The endogenous production of active TGF-beta was shown to regulate inflammatory gene expression by demonstrating that: 1) beta 1,3-glucan stimulated both TGF-beta mRNA expression and protein release into conditioned media; 2) supernatants from stimulated macrophages primed for lysosomal hydrolase synthesis, and this effect was blocked by anti-TGF-beta antibodies; and 3) anti-TGF-antibodies blocked beta 1,3-glucan-stimulated lysosomal hydrolase synthesis. Collectively, these data describe a novel function for TGF-beta as a priming agent for macrophage inflammatory gene expression and suggest a mechanism for local amplification of the inflammatory response.