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Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled
1Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Abstract:
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.
Insights
Inhaled isobutyl nitrite impairs macrophage tumoricidal activity by disrupting NF-kappaB signaling. This study reveals how nitrite inhalants compromise immune function, potentially linking to conditions like Kaposi
Area of Science:
- Immunology
- Toxicology
Background:
- Nitrite inhalant abuse is linked to HIV seropositivity and Kaposi's sarcoma.
- Macrophages play a crucial role in tumoricidal activity and immune responses.
Purpose of the Study:
- To investigate the effects of isobutyl nitrite inhalation on macrophage function.
- To elucidate the molecular mechanisms underlying nitrite inhalant-induced immunomodulation.
Main Methods:
- Mice were exposed to 900-ppm isobutyl nitrite daily for 14 days.
- Peritoneal exudate macrophages (PEM) and resident peritoneal macrophages (RPM) were analyzed for cell counts, cytotoxicity, nitric oxide (NO) induction, inducible NO synthase (iNOS) protein levels, and NF-kappaB pathway activation.
- Proteasome activity was assessed in macrophages from exposed mice.
Main Results:
- Isobutyl nitrite inhalation significantly reduced PEM (35%) and RPM (18%) counts.
- PEM cytotoxicity decreased by 26%, while RPM tumoricidal activity remained unaffected.
- Nitric oxide induction and iNOS protein levels in PEM were inhibited.
- NF-kappaB activation was suppressed due to reduced degradation of IkappaB alpha, linked to compromised proteasome activity.
Conclusions:
- Inhaled isobutyl nitrite impairs macrophage tumoricidal activity, particularly affecting PEM.
- The mechanism involves the inhibition of NF-kappaB pathway activation via compromised proteasomal degradation of IkappaB alpha.
- These findings provide insights into the immunomodulatory effects of nitrite inhalants and their potential role in associated health conditions.
