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caveolin-1: a critical regulator of inflammation and fibrosis

Wang, Xiaomei (2006) caveolin-1: a critical regulator of inflammation and fibrosis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Caveolin-1 (cav-1) has been reported to regulate apoptosis, lipid metabolism and endocytosis. In the present study, we demonstrate that cav-1 can act as a potent immunomodulatory molecule in murine macrophages and play an important role in the development of fibrosis. In murine alveolar and peritoneal macrophages, loss of function experiments using siRNA showed that down-regulating cav-1 expression increased lipopolysaccharide (LPS)-induced proinflammatory cytokine tumor necrosis factor-alpha (TNF-á) and interleukin-6 (IL-6) production but decreased anti-inflammatory cytokine interleukin-10 (IL-10) production. Gain of function experiments demonstrated that overexpression of cav-1 in RAW264.7 decreased LPS-induced TNF-á and IL-6 production and augmented IL-10 production. Cav-1 interacted with TLR4 as revealed by co-immunoprecipitation in peritoneal macrophages. Overexpressing cav-1 in RAW264.7 disrupted Toll like receptor 4 (TLR4) MyD88 and TRIF complex formation; regulated mitogen-activated protein kinase (MAPK) phosphorylation; and inhibited NF-êB activation. Furthermore, the anti-inflammatory modulation by cav-1 involved p38, since the administration of SB203580 significantly abrogated the effects of cav-1, and peritoneal macrophages isolated from MKK3 null mice did not demonstrate any modulation of cav-1. Interestingly, HO-1 translocated into caveolae after LPS stimulation. Carbon monoxide (CO), the gaseous byproduct of HO activity responsible for the anti-inflammatory effects of HO-1, did not regulate cytokines production in cav-1 null macrophages. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients, compared to controls. Transforming growth factor-â1 (TGF-â1), the well-known pro-fibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. Cav-1 was able to suppress TGF-â1-induced extracellular matrix (ECM) production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF and bleomycin (BLM)-instilled lung tissue samples, which was dramatically suppressed by adenovirus cav-1 infection. Moreover, JNK1 null fibroblasts showed reduced Smads cascades signaling, mimicking the effects of cav-1. We also demonstrated that cav-1 markedly ameliorated BLM-induced pulmonary fibrosis as evidenced by histological analysis, hydroxyproline content and immunoblot analysis. In summary, our data suggest that cav-1 acts as a potent immunomodulatory and anti-fibrotic effector molecule. Cav-1 may mediate the anti-inflammatory effects of HO-1/CO in immune cells involving the MKK3/p38 MAPK pathway. Cav-1 also plays a pivotal role in ECM regulation and the development of fibrosis, possibly through the MAPK and Smads pathway. This study suggests cav-1 as a novel therapeutic target for patients with fibrosis and inflammation.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wang, Xiaomeiwxmpost@hotmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBowser, Robert Pbowserrp@upmc.edu
Committee MemberChoi, Augustine M.Kchoiam@upmc.edu
Committee MemberPitt, Bruce Rbrucep@pitt.eduBRUCEP
Committee MemberOury, Tim Dtdoury@pitt.eduTDOURY
Committee MemberYin, Xiao-Mingxmyin@pitt.eduXMYIN
Date: 13 December 2006
Date Type: Completion
Defense Date: 1 November 2006
Approval Date: 13 December 2006
Submission Date: 7 December 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: caveolin-1; fibrosis; inflammation
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12072006-155317/, etd-12072006-155317
Date Deposited: 10 Nov 2011 20:08
Last Modified: 15 Nov 2016 13:53
URI: http://d-scholarship.pitt.edu/id/eprint/10142

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