Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

Gu H., Mickler E.A., Cummings O.W., Sandusky G.E., Weber D.J., Gracon A., Woodruff T., Wilkes D.S. and Vittal R. (2014) Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis. FASEB Journal, 28 10: 4223-4234. doi:10.1096/fj.13-247650


Author Gu H.
Mickler E.A.
Cummings O.W.
Sandusky G.E.
Weber D.J.
Gracon A.
Woodruff T.
Wilkes D.S.
Vittal R.
Title Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis
Journal name FASEB Journal   Check publisher's open access policy
ISSN 0892-6638
1530-6860
Publication date 2014-10-01
Year available 2014
Sub-type Article (original research)
DOI 10.1096/fj.13-247650
Open Access Status
Volume 28
Issue 10
Start page 4223
End page 4234
Total pages 12
Place of publication Bethesda, MD United States
Publisher FASEB
Collection year 2015
Language eng
Formatted abstract
The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex–mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor β1 (TGF-β1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-β1 in complement activation–mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-β1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-β1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-β), and whereas TGF-β1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-β1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-β1 expression.—Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis.
Keyword Cluster of differentiation(CD55)
Idiopathic pulmonary fibrosis(IPF)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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