Superoxide attenuates macrophage apoptosis by NF-kappa B and AP-1 activation that promotes cyclooxygenase-2 expression.

Abstract

Macrophages are a major source of cytokines and proinflammatory radicals such as superoxide. These mediators can be both produced and utilized by macrophages in autocrine-regulatory pathways. Therefore, we studied the potential role of oxygen radical-regulatory mechanisms in reprogramming macrophage apoptosis. Preactivation of RAW 264.7 cells with a nontoxic dose of the redox cycler 2,3-dimethoxy-1,4-naphthoquinone (5 microM) for 15 h attenuated S-nitrosoglutathione (1 mM)-initiated apoptotic cell death and averted accumulation of the tumor suppressor p53, which is indicative for macrophage apoptosis. Preactivation with superoxide promoted cyclooxygenase-2 induction that was NF-kappa B and AP-1 mediated. NF-kappa B activation was confirmed by p50/p65-heterodimer formation, I kappa B-alpha degradation, and stimulation of a NF-kappa B luciferase reporter construct. Furthermore, a NF-kappa B decoy approach abrogated cyclooxygenase-2 (Cox-2) expression as well as inducible protection. The importance of AP-1 for superoxide-mediated Cox-2 expression and cell protection was substantiated by using the extracellular signal-regulated kinase-inhibitor PD98059 and the p38-inhibitor SB203580, which blocked Cox-2 expression. In corroboration, Cox-2 expression was hindered by a dominant-negative c-jun mutant (TAM67). Protection from apoptosis was verified in human macrophages with the notion that superoxide promoted Cox-2 expression, which in turn attenuated nitric oxide-evoked caspase activation. We conclude that the sublethal generation of oxygen radicals reprograms macrophages by NF-kappa B and AP-1 activation. The resulting hyporesponsiveness reveals an attenuated apoptotic program in association with Cox-2 expression.

• Authors: A von Knethen, D Callsen, B Brüne
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 163 Issue 5 Pg. 2858-66 (Sep 01 1999) ISSN: 0022-1767 [Print] United States
• PMID: 10453032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Isoenzymes
• NF-kappa B
• Naphthoquinones
• Transcription Factor AP-1
• Tumor Suppressor Protein p53
• Superoxides
• Nitric Oxide
• 2,3-dimethoxy-1,4-naphthoquinone
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Apoptosis (drug effects, immunology)
• Cell Line
• Cyclooxygenase 2
• Dose-Response Relationship, Drug
• Isoenzymes (biosynthesis, metabolism)
• Macrophages (cytology, drug effects, enzymology, metabolism)
• Mice
• NF-kappa B (metabolism, physiology)
• Naphthoquinones (pharmacology)
• Nitric Oxide (physiology)
• Prostaglandin-Endoperoxide Synthases (biosynthesis, metabolism)
• Superoxides (pharmacology)
• Transcription Factor AP-1 (metabolism, physiology)
• Tumor Suppressor Protein p53 (metabolism)