Elevated levels of NO in both unchallenged and LPS-challenged C. parvum-primed mice are attributable to the activity of a cytokine-inducible isoform of iNOS.
Elevated levels of nitric oxide (NO2-/NO3-) were detected in the serum of mice 3-7 days after priming with Corynebacterium parvum (Propionibacterium acnes). The serum NO2-/NO3- response was completely inhibited when C. parvum-primed (C. parrum) mice were treated with N(G)-monomethyl-L-arginine (L-NMMA) or aminoguanidine (AG) on days 6 and 7 post priming. The response was also inhibited when the mice were treated with interleukin-10 (IL-10) and the cytokine was most effective when given in multiple doses beginning on the day of priming. In contrast to L-NMMA and AG, IL-10 had no effect on the serum NO2-/NO3- response when administered to the mice on days 6 and 7 post priming. The inducible isoform of NOS (iNOS) appeared to be responsible for the elevated NO2-/NO3- response in C. parvum mice because iNOS transcripts were readily detected in their livers. Moreover, these transcripts as well as the circulating levels of NO2-/NO3- were dramatically reduced when the mice were treated with anti-tumor necrosis factor alpha (anti-TNF-alpha) or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibodies (mAbs) during the priming interval. There was a modest increase (less than twofold) in the serum NO2-/NO3- response following a lipopolysaccharide (LPS) challenge to C. parvum mice (C. parvum/LPS mice). LPS had a more dramatic stimulatory effect if the levels of NO2-/NO3- preexisting in C. parvum/LPS mice were reduced by treatment with L-NMMA, AG, or IL-10 before the challenge. Thus the levels of NO2-/NO3- that preexisted in C. parvum/LPS mice appeared to influence their ability to mount a NO2-/NO3- response subsequent to the LPS challenge. The NO2-/NO3- response did not contribute to lethality in C. parvum/LPS mice because anti-TNF-alpha and anti-IFN-gamma mAbs were protective but had no effect on serum NO2-/NO3- levels when administered to mice 24 h before the LPS challenge.
Smith
S R
SR
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Manfra
D
D
Davies
L
L
Terminelli
C
C
Denhardt
G
G
Donkin
J
J
D000818:Animals; D006146:Guanidines / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D016753:Interleukin-10 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009566:Nitrates / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009573:Nitrites / Q000097:blood*; D011425:Propionibacterium acnes; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D006146:Guanidines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; C004479:pimagedine