Inhibition of bacterial cell wall-induced leukocyte recruitment and hepatic granuloma formation by TGF-beta gene transfer

Intraperitoneal injection of streptococcal cell walls (SCW) into Lewis rats results in dissemination of SCW to the liver, spleen, bone marrow, and per ipheral joints. The uptake of SCW by Kupffer cells in the liver initiates a chain of events largely mediated by T lymphocytes and macrophages. Local s ynthesis and secretion of cytokines and growth factors in response to the p ersistent SCW lead to the evolution and maintenance of a chronic T cell-dep endent granulomatous response and result in granuloma formation and irrever sible hepatic fibrosis, In an attempt to impede the development of the chro nic granulomatous lesions in the liver, we injected a plasmid DNA encoding TGF-beta 1 i.m. to the SCW animals to determine the effect of TGF-beta 1 ge ne transfer on the course of liver inflammation and fibrosis, A single inje ction of plasmid DNA encoding TGF-beta 1 resulted in virtual abolition of t he development of the SCW-induced hepatic granuloma formation and matrix ex pansion. TGF-beta 1 DNA not only reduced key proinflammatory cytokines incl uding TNF-alpha, IL-1 beta, IFN-gamma, and IL-18, but also inhibited both C XC and CC chemokine production, thereby blocking inflammatory cell recruitm ent and accumulation in the liver. Moreover, TGF-beta 1 gene delivery inhib ited its own expression in the liver tissue, which is otherwise up-regulate d in SCW-injected animals. Our study suggests that TGF-beta 1 gene transfer suppresses hepatic granuloma formation by blocking the recruitment of infl ammatory cells to the liver, and thus mag provide a new approach to the con trol of hepatic granulomatous and fibrotic diseases.