Enhanced activity of human IL-10 after nitration in reducing human IL-1 production by stimulated peripheral blood mononuclear cells.
Nitric oxide and superoxide form the unstable compound, peroxynitrite, which can nitrate proteins and compromise function of proinflammatory cytokines at sites of inflammation. Reduced function of proinflammatory proteins such as IL-8, macrophage inflammatory protein-1alpha, and eotaxin suggest an anti-inflammatory effect of nitration. The effects of nitration on anti-inflammatory cytokines such as IL-10 are unknown. We hypothesized that peroxynitrite would modify the function of anti-inflammatory cytokines like IL-10. To test this hypothesis, the capacity of recombinant human IL-10 to inhibit production of human IL-1beta (IL-1) from LPS-stimulated human PBMC was evaluated. Human IL-10 was nitrated by incubation with peroxynitrite or by incubation with 3-morpholinosydnonimine, a peroxynitrite generator, for 2 h and then incubated with LPS-stimulated PBMC for 6 h, and IL-1 was measured in the culture supernatant fluids. Human IL-1 production was significantly lower in the peroxynitrite- or 3-morpholinosydnonimine-nitrated IL-10 group than in the IL-10 controls (p < 0.05, all comparisons). This finding demonstrates that although peroxynitrite inhibits proinflammatory cytokines, it may augment anti-inflammatory cytokines and further point to an important role for peroxynitrite in the regulation of inflammation.
Freels
Jon L
JL
Research Service, Southern Arizona Veterans Health Care System, Arizona Respiratory Sciences, University of Arizona, 3601 South 6th Avenue, Tucson, AZ 85723, USA.
Nelson
Dan K
DK
Hoyt
Jeffrey C
JC
Habib
Michael
M
Numanami
Hiroki
H
Lantz
R Clark
RC
Robbins
Richard A
RA
D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D019163:Reducing Agents / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D019163:Reducing Agents; D016753:Interleukin-10; D030421:Peroxynitrous Acid; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine; D003676:Deferoxamine; D004229:Dithiothreitol