Inducible nitric oxide synthase attenuates chronic colitis in HLA-B27/human beta 2-microglobulin transgenic rats

Rats transgenic for HLA-B27/human beta (2)-microglobulin develop a spontane ous multisystem inflammatory disorder that closely mimicks human spondyloar thropathies Prominent features of this disorder are gut inflammation that p redominates in the colon, and arthritis. Several mediators such as IFN-gamm a, IL-1 beta, TNF-alpha, and inducible nitric oxide synthase (iNOS) have be en found increased in the inflamed colonic mucosa, In the colon of HLA-B27 transgenic rats, iNOS is predominantly expressed by epithelial cells, and i NOS transcripts are detected in the hip cartilage of those rats, but not in nontransgenic littermates. The role of iNOS in this disorder was evaluated by administering the corticosteroid dexamethasone, or the NOS inhibitor L- N-6-(1-iminoethyl)lysine (L-NIL) to HLA-B27 transgenic rats with establishe d disease. Treatment with dexamethasone attenuated some aspects of gut infl ammation, although it had no effect on iNOS expression. In contrast, treatm ent with L-NIL effectively inhibited iNOS activity, and resulted in an incr ease in colitis. Cytokine transcripts in the colon were modified by these t reatments: IFN-gamma and IL-1 beta were decreased after dexamethasone treat ment, whereas administration of L-NIL resulted in decreased IFN-gamma, and TNF-alpha, A trend towards increased IL-1 beta expression was observed whic h could have contributed to the L-NIL pro-inflammatory effect. These result s suggest that iNOS exerts a protective effect on colitis, in the inflammat ory disorder of HLA-B27 transgenic rats.