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Schistosomiasis Immunology and Pathology Unit, Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Biomedical Research Institute, Rockville, MD 20852; and
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263
Hepatic fibrosis is the hallmark of Schistosoma
mansoni infection and often results in portal hypertension and
bleeding from esophageal varices. The fibrotic process is highly
dependent on type 2 cytokines, yet their role in the regulation of
extracellular matrix remodeling genes remains largely unknown. Here, we
examined the expression of matrix metalloproteases (MMP) -2, -3, -9,
-12, and -13 and their inhibitors, tissue inhibitor of metalloproteases
(TIMP) -1, -2, and -3, in the livers of infected mice and correlated
their expression profiles with fibrosis and type 2 cytokine production.
Expression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA
rapidly increased at the onset of egg laying in infected mice, while
TIMP-3 was unchanged. Because TIMP are presumed to be important
regulators of the extracellular matrix, and their expression correlated
with the development of fibrosis, we studied their role in fibrogenesis
by infecting TIMP-1- and TIMP-2-deficient mice. Strikingly, our data
revealed no role for TIMP-1 or -2 in the fibrotic pathology induced by
S. mansoni eggs. Because of these findings, we infected
IL-10/IFN-
-deficient mice that develop an exaggerated fibrotic
response to determine whether changes in type 2 cytokine dominance
influence the pattern of MMP and TIMP expression. Fibrosis and type 2
cytokine production correlated with increased MMP-2/MMP-9 vs
TIMP-1/TIMP-2 expression. These data, in addition to our knockout
studies, demonstrate that TIMP-1/TIMP-2 play no essential role in
fibrogenesis in schistosomiasis. Indeed, our findings suggest that
inhibiting profibrotic cytokines or specific MMP may be a more
effective strategy to ameliorate fibrotic
pathology.
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