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Peroxynitrite Enhances Interleukin-10 Reduction in the Release of Neutrophil Chemotactic Activity

Research Service, Southern Arizona Veterans Health Care System, and Arizona Respiratory Center, University of Arizona, Tucson, Arizona; Second Department of Surgery, and First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

Address correspondence to: Richard A. Robbins, M.D., Chief, Research Service Line, Southern Arizona Veterans Health Care System, 3601 S. 6th Avenue, Tucson, AZ 85723. E-mail: Richard.Robbins2{at}med.va.gov

Peroxynitrite, formed by nitric oxide and superoxide, has been shown to nitrate and reduce the function of proinflammatory proteins such as interleukin (IL)-8, monocyte chemoattractant protein-1, and eotaxin, but in contrast, to enhance the function of the anti-inflammatory cytokine IL-10 in reducing IL-1 release from blood monocytes. However, the effect of nitrated IL-10 on release of proinflammatory cytokines from lung epithelial cells is unknown. We hypothesized that peroxynitrite would enhance the capacity of human IL-10 to reduce inflammatory mediators released by epithelial cells. To test this hypothesis, recombinant human IL-10 was evaluated for its capacity to attenuate the release of neutrophil chemotactic activity and IL-8 from a human epithelial cell line in response to IL-1ß and tumor necrosis factor-. Neutrophil chemotactic activity and IL-8 in lung epithelial culture supernatant fluids were significantly lower after culture with nitrated human IL-10 compared with non-nitrated human IL-10 controls (P < 0.05). Consistent with these results, nitrated human IL-10 attenuated IL-8 mRNA expression more than non-nitrated human IL-10 controls (P < 0.05). These data demonstrate that peroxynitrite exposed human IL-10 has enhanced anti-inflammatory activity and suggest that nitration may play a critical role in the regulation of inflammation within the lower respiratory tract.

Abbreviations: enzyme-linked immunosorbent assay, ELISA • high-power fields, HPF • interleukin, IL • neutrophil chemotactic activity, NCA • regulated upon activation, normal T cell expressed and presumably secreted, RANTES • reverse transcriptase-polymerase chain reaction, RT-PCR • tumor necrosis factor-, TNF-