Regulation of hepatic fibrosis and extracellular matrix genes by the Th response: New insight into the role of tissue inhibitors of matrix metalloproteinases

Hepatic fibrosis is the hallmark of Schistosoma mansoni infection and often results in portal hypertension and bleeding from esophageal varices. The f ibrotic process is highly dependent on type 2 cytokines, yet their role in the regulation of extracellular matrix remodeling genes remains largely unk nown. Here, we examined the expression of matrix metalloproteases (MMP) -2, -3, -9, -12, and -13 and their inhibitors, tissue inhibitor of metalloprot eases (TIMP) -1, -2, and -3, in the livers of infected mice and correlated their expression profiles with fibrosis and type 2 cytokine production. Exp ression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA rapidly in creased at the onset of egg laying in infected mice, while TIMP-3 was uncha nged. Because TIMP are presumed to be important regulators of the extracell ular matrix, and their expression correlated with the development of fibros is, we studied their role in fibrogenesis by infecting TIMP-1- and TIMP-2-d eficient mice. Strikingly, our data revealed no role for TIMP-1 or -2 in th e fibrotic pathology induced by S. mansoni eggs. Because of these findings, we infected IL-10/IFN-gamma -deficient mice that develop an exaggerated fi brotic response to determine whether changes in type 2 cytokine dominance i nfluence the pattern of MMP and TIMP expression. Fibrosis and type 2 cytoki ne production correlated with increased MMP-2/MMP-9 vs TIMP-1/TIMP-2 expres sion. These data, in addition to our knockout studies, demonstrate that TIM P-1/TIMP-2 play no essential role in fibrogenesis in schistosomiasis. Indee d, our findings suggest that inhibiting profibrotic cytokines or specific M MP may be a more effective strategy to ameliorate fibrotic pathology.