Role of inducible nitric oxide synthase in the regulation of neutrophil migration in zymosan-induced inflammation

In the present study, by comparing the responses in wild-type mice and mice lacking the inducible (or type 2) nitric oxide synthase (iNOS), we investi gated the role played by iNOS in the regulation of polymorphonuclear granul ocyte (PMN) accumulation and chemokine production in the mouse peritoneal c avity in response to administration of zymosan (0.2 mg). Zymosan injection induced the production of nitric oxide, and triggered a time-dependent PMN immigration into the peritoneal cavity. This response was associated with i ncreases in the level of the chemokines macrophage inflammatory protein (MI P)-1 alpha, MIP-2, monocyte chemo-attractant protein (MCP)-1 and cytokine-i nduced neutrophil chemo-attractant (KC), as measured in the peritoneal cavi ties. Injection of zymosan also induced a time-dependent increase in the pr oduction of the antiinflammatory cytokine interleukin-10 (IL-10) in the per itoneal cavity. When comparing the response between wild-type and iNOS knoc kout (KO) mice, we observed that the low-level PMN accumulation measured at 1 hr was slightly but significantly increased in the absence of functional iNOS. On the other hand, the delayed response (2-4 hr after zymosan) of PM N accumulation was suppressed in,the iNOS KO mice. The early enhancement of PMN infiltration in the iNOS-deficient mice: was associated with increased peritoneal levels of MIP-2, KC and IL-10 proteins. The delayed suppression of PMN infiltration was associated with reduced MIP-2 and IL-10 levels in the peritoneal cavity. The lack of iNOS did not affect the release of MIP-1 alpha and MCP-1 at any of the time-points studied. The current data demons trate that iNOS regulates the production of certain CXC (but not CC) proinf lammatory chemokines, the production of IL-IO and exerts a biphasic regulat ory effect on PMN accumulation in zymosan-induced acute inflammation.