Blockade of iNOS prolongs the survival of rat to mouse skin xenograft by suppressing Th1 cytokines

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Abstract 506
Introduction Since we have previously observed that both INF-γ mRNA and inducible nitric oxide synthase (iNOS) levels were much higher in skin xenograft than allograft, the present study focuses on the effects of iNOS inhibition on skin xenograft survival and Th1 and Th2 cytokine expression. Even though it has been well documented that iNOS is up-regulated in the rejection of allografts and that its inhibition by potent inhibitors prolongs allograft survival research has not been carried out into such effects in xenografts.
Materials and methods To elucidate the role of NO in xenograft rejection, C57BL/6 J mice were grafted with Lewis rat tail skin. The mice were injected intraperitoneally with potent inhibitors of iNOS; aminoguanidine (AMG, 200 mg/kg) and NG-nitro-L-arginine methyl ester (NAME, 60 mg/kg). Graft survival and cytokine mRNA expression levels were measured by real-time RT-PCR in context with iNOS expression on days 1, 3, 5, 7 and 9. These data were compared with those of control mice (saline injected).
Results On day 7, the levels of cytokines such as IL-1β, IL-2, IL-6, IL-10, IL-12, IFN-γ and TGF-β1 and of iNOS were markedly increased (P < 0.01). Compared with the control mice, xenograft rejection was delayed in the AMG- or NAME-treated mice by approximately 3 days (8.5 ± 0.6 days vs. 11.7 ± 1.2 and 12.0 ± 0.0 days, control, AGM, and NAME, respectively). In addition, the up-regulated levels of pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-12, and IFN-γ were significantly suppressed (P < 0.01) whereas the Th2 cytokine levels (IL-10 and TGF-β1) did not evidence any significant change.
Conclusion These data showed that NO suppression by iNOS inhibitors may prolong rat to mouse skin xenograft survival by the selective inhibition of pro-inflammatory cytokines. This finding suggests that NO may act on xenogeneic immune response as an immune modulator by shifting the Th1/Th2 paradigm, as well as functioning as a cytotoxic effector.
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