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Published ahead of print on December 15, 2005, doi:10.1165/rcmb.2005-0376OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 4, April 2006, 434-442

A more recent version of this article appeared on April 1, 2006
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Submitted on October 6, 2005
Revised on December 12, 2005

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

Xiao Mei Wang1, Hong Pyo Kim1, Ruiping Song1, and Augustine M.K. Choi1*

1 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

* To whom correspondence should be addressed. E-mail: ChoiAM{at}UPMC.EDU.

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 siRNA showed that down-regulating caveolin-1 expression in murine alveolar and peritoneal macrophages increased lipopolysaccharide (LPS)-induced pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-{alpha}) and interleukin-6 (IL-6) production but decreased anti-inflammatory cytokine interleukin-10 (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. Interestingly, p38 mitogen-activated protein kinase (MAPK) phosphorylation was increased by overexpressing caveolin-1 in RAW264.7 cells, whereas c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) MAPK and Akt phosphorylation were inhibited. Furthermore, the anti-inflammatory modulation of LPS-induced cytokine production by caveolin-1 was significantly abrogated by the administration of p38 inhibitor SB203580 in RAW264.7 cells. Interestingly, 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-{kappa}B and AP-1 determined by EMSA were significantly reduced by over-expressing 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 effecter molecule in immune cells and the regulation of LPS-induced cytokine production by caveoilin-1 involves the MKK3/p38 MAPK pathway.




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