Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite.
A history of abuse of nitrite inhalants has been correlated with HIV seropositivity and Kaposi's sarcoma. A series of 14 daily, 45-min exposures of mice to 900-ppm isobutyl nitrite in an inhalation chamber reduced the number of peritoneal exudate macrophages (PEM) by 35% and the number of resident peritoneal macrophages (RPM) by 18%. Although the tumoricidal activity of RPM was not affected by the inhalant, the cytotoxicity of PEM was reduced by 26%. The induction of nitric oxide (NO) and the inducible NO synthase (iNOS) protein in PEM were inhibited by the inhalant to a similar extent. Inhibition of NF-kappaB activation in PEM from mice exposed to the inhalant corresponded to reduced degradation of the NF-kappaB inhibitor, IkappaB alpha. Proteasome-associated, enzymatic activity was compromised in PEM from inhalant-exposed mice, suggesting that inhaled isobutyl nitrite compromised macrophage, tumoricidal activity by inhibiting proteasomal degradation of the NF-kappaB inhibitor, IkappaB alpha.
Ponnappan
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Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Soderberg
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LS
D000280:Administration, Inhalation; D000818:Animals; D002073:Butanes / Q000494:pharmacology* / Q000633:toxicity; D003546:Cysteine Endopeptidases; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003864:Depression, Chemical; D004198:Disease Susceptibility; D005260:Female; D015658:HIV Infections / Q000453:epidemiology; D007111:Immunity, Cellular / Q000187:drug effects*; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced*; D007249:Inflammation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009566:Nitrates / Q000494:pharmacology* / Q000633:toxicity; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex; D012307:Risk Factors; D012514:Sarcoma, Kaposi / Q000453:epidemiology; D019966:Substance-Related Disorders; D014407:Tumor Cells, Cultured
D002073:Butanes; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009566:Nitrates; D009569:Nitric Oxide; C069055:isobutyl nitrate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex