Caveolin-1 Confers Antiinflammatory Effects in Murine Macrophages via the MKK3/p38 MAPK Pathway

Abstract

Caveolin-1 has been reported to regulate apoptosis, lipid metabolism, and endocytosis in macrophages. In the present study, we demonstrate that caveolin-1 can act as a potent immunomodulatory molecule. We first observed caveolin-1 expression in murine alveolar macrophages by Western blotting and immunofluorescence microscopy. Loss-of-function experiments using small interfering RNA showed that down regulating caveolin-1 expression in murine alveolar and peritoneal macrophages increased LPS-induced proinflammatory cytokine TNF-alpha and IL-6 production but decreased anti-inflammatory cytokine IL-10 production. Gain-of-function experiments demonstrated that overexpression of caveolin-1 in RAW264.7 cells decreased LPS-induced TNF-alpha and IL-6 production and augmented IL-10 production. p38 mitogen-activated protein kinase (MAPK) phosphorylation was increased by overexpressing caveolin-1 in RAW264.7 cells, whereas c-Jun N-terminal kinase, extracellular signal-regulated kinase MAPK, and Akt phosphorylation were inhibited. The antiinflammatory modulation of LPS-induced cytokine production by caveolin-1 was significantly abrogated by the administration of p38 inhibitor SB203580 in RAW264.7 cells. Peritoneal macrophages isolated from MKK3 null mice did not demonstrate any modulation of LPS-induced cytokine production by caveolin-1. LPS-induced activation of NF-kappaB and AP-1 determined by electrophoretic mobility shift assay were significantly reduced by overexpressing caveolin-1 in RAW264.7 cells. The reductions were attenuated by the administration of p38 inhibitor SB203580. Taken together, our data suggest that caveolin-1 acts as a potent immunomodulatory effector molecule in immune cells and that the regulation of LPS-induced cytokine production by caveolin-1 involves the MKK3/p38 MAPK pathway.

Molecular Characterization of Caveolin-1 in Pigs Infected with Haemophilus parasuis

“…Most of the transcription factor binding sites are also present in the human and bovine genes, suggesting that the regulation of caveolin-1 expression is conserved among mammals. These observations are supported by previous reports showing that activation of protein kinase A downregulates caveolin-1 protein expression (66) and that cytokine production by caveolin-1 also involves the MAPK kinase 3/p38 MAPK pathway (67).…”

Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

“…Other potentially important sequelae of cav-1 deletion may include altered regulation of apoptosis and inflammation as suggested by other recent studies (20,22). These additional functions of cav-1 may be relevant since pulmonary hypertension is associated with endothelial cell-specific apoptosis and considerable vascular inflammation.…”

Kainic acid induces expression of caveolin-1 in activated microglia in rat brain

“…For example, caveolin-1 deficient macrophages display impaired phagocytosis [19]. Wang et al [20] demonstrated that caveolin-1 acts as a potent immunomodulatory effecter molecule in murine alveolar and peritoneal macrophages. They showed that caveolin-1 has a protective role for inflammation by suppression of pro-inflammatory cytokine production (TNF-a and IL-6) and augmentation of anti-inflammatory cytokine production (IL-10) [20].…”

“…Wang et al [20] demonstrated that caveolin-1 acts as a potent immunomodulatory effecter molecule in murine alveolar and peritoneal macrophages. They showed that caveolin-1 has a protective role for inflammation by suppression of pro-inflammatory cytokine production (TNF-a and IL-6) and augmentation of anti-inflammatory cytokine production (IL-10) [20]. Thus, it is tempting to speculate that caveolin-1 in activated microglia participates in modulation of inflammation in the brain in response to excitotoxic insults.…”