Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Abstract

Alveolar macrophages (AM) and inflammatory mediators including nitric oxide and peroxynitrite contribute to ozone-induced lung injury. The generation of these mediators is regulated, in part, by the transcription factor NF-κB. We previously demonstrated a critical role for NF-κB p50 in the ozone-induced injury. In the present studies mechanisms regulating NF-κB activation in the lung after ozone inhalation were analyzed. Treatment of wild type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-κB binding activity in AM, which persisted for at least 12 h. This was not evident in mice lacking TNFα which are protected from ozone-induced injury; there was also no evidence of nitric oxide or peroxynitrite production in lungs from these animals. These data demonstrate that TNFα plays a role in NF-κB activation and toxicity. TNFα signaling involves PI-3-kinase (PI3K)/protein kinase B (PKB), and p44/42 MAP kinase (MAPK) which are important in NF-κB activation. Ozone Inhalation resulted in rapid and transient increases in p44/42 MAPK and PI3K/PKB in AM from WT mice, which was evident immediately after exposure. Caveolin-1, a transmembrane protein that negatively regulates PI3K/PKB and p44/42 MAPK signaling, was downregulated in AM from WT mice after ozone exposure. In contrast, ozone had no effect on caveolin-1, PI3K/PKB or p44/42 MAPK expression in AM from TNFα knockout mice. These data, together with our findings that TNFα suppressed caveolin-1 in cultured AM, suggest that TNFα and downstream signaling mediate activation of NF-κB and the regulation of inflammatory genes important in ozone toxicity, and that this process is linked to caveolin-1.

The Genome-Wide Expression Profile of Nelumbinis semen on Lipopolysaccharide-Stimulated BV-2 Microglial Cells

“…Additionally, knockout studies in mice have suggested that TNF-a deletion exerts a neuroprotective function. 36,37) In this study, ELISA analysis revealed that TNF-a production was significantly inhibited by 1 mg/ml NS (Fig. 2), which indicates that NS exerts its effects via a pathway that protects cells from neuroinflammatory cytokine regulation (Fig.…”

Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease

“…The proinflammatory cytokine TNFα and the profibrotic cytokine TGFβ have major roles in inflammation and fibrosis in scleroderma1 and have been shown to inhibit caveolin-1 expression in other cell types 18 19 23. We therefore examined the possibility that these treatments might inhibit caveolin-1 expression in monocytes.…”

Bone marrow-derived macrophages exclusively expressed caveolin-2: The role of inflammatory activators and hypoxia

“…It was described that caveolin-1 has a protective role during inflammation by suppressing the production of pro-inflammatory mediators (e.g. TNF␣ and IL-6) and promoting the anti-inflammatory response in macrophages (Ben et al, 2013;Fakhrzadeh, 2008;Wang et al, 2006). One of the few known facts about the connection of caveolins with signal transduction is the initiation of MAPK pathways after stimulation of macrophages by classical activators (Feng et al, 2013).…”

“…and are responsible for production of a wide spectrum of pro-inflammatory mediators (e.g. NO and tumor necrosis factor alpha, TNF␣) (Burke et al, 2003;Talks et al, 2000;Ben et al, 2013;Laskin et al, 2010;Fakhrzadeh, 2008;Parameswaran and Patial, 2010). Importantly, when recruited to tissue sites of infection or inflammation, macrophages immediately encounter a decreasing oxygen gradient, which leads to stabilization of hypoxia inducible factor-1 alpha (HIF-1␣) protein.…”