Challenge of Lewis (LEW/N) rats with SCW induces acute and chronic inflammation in peripheral joints, liver, and spleen. In contrast, the inbred MHC compatible Fischer strain (F344/N) does not develop chronic inflammatory and autoimmune-like disease. To identify potential differences at the genetic level which might contribute to the phenotypic differences between the LEW/N and F344/N strains, animals of both strains were injected with SCW, and a subtracted cDNA library (LEW/N - F344/N) was generated from peritoneal exudate cells. Subsequent analysis of differentially expressed genes revealed clones which exhibit homology to human migration inhibitory factor-related proteins (MRP). These calcium- binding proteins form complexes, are expressed by circulating monocytes and neutrophils and are expressed during the development of arthritis. The correlation of MRP8 and MRP14 expression with genetic susceptibility to the development of chronic inflammation in response to bacterial cell wall antigens provides new opportunities for defining molecular mechanisms responsible for potentially pathologic inflammatory diseases. In additional studies, peptides synthesized from fibronectin which inhibited leukocyte adhesion in vitro were administered to arthritic animals either as free peptides or coupled to a carrier molecule. Peptides containing either the RGD or CS-1 cell-binding domains were inhibitory to chronic synovial pathology, as were three peptides synthesized from the carboxyl terminal 33 kD heparin-binding domain. Since transforming growth factor beta (TGF-beta) induces leukocytes adhesion, antagonism of TGF-beta with a neutralizing antibody also blocked inflammatory cell accumulation and tissue pathology in this model. These data implicate TGF-beta as a profound antagonist not only in the early events responsible for synovial inflammation, but also in the chronicity of SCW-fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists or synthetic peptides may provide mechanisms for resolution of chronic destructive lesions.
