Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2.
CC chemokine receptor 2 (CCR2) -/- mice are protected from experimental pulmonary fibrosis, a disease increasingly recognized as being mediated by dysfunctional interactions between epithelial cells and fibroblasts. We have sought to investigate the interactions between alveolar epithelial cells (AECs) and fibroblasts in these fibrosis-resistant (CCR2 -/-) and fibrosis-sensitive (CCR2 +/+) mice. AECs from CCR2 -/- mice suppress fibroblast proliferation more than AECs from CCR2 +/+ mice (77 vs. 43%). Exogenous administration of the CCR2 ligand monocyte chemoattractant protein-1 (MCP-1) to the fibroblast-AEC cocultures reverses the suppression mediated by CCR2 +/+ AECs but has no effect with CCR2 -/- AECs. MCP-1 regulates AEC function but not fibroblast function. AEC inhibition of fibroblast proliferation was mediated by a soluble, aspirin-sensitive factor. Accordingly, AECs from CCR2 -/- mice produce greater quantities of PGE(2) than do AECs from CCR2 +/+ mice, and MCP-1 inhibits AEC-derived PGE(2) synthesis. Diminished PGE(2) production by AECs results in enhanced fibroproliferation. Thus an important profibrotic mechanism of MCP-1/CCR2 interactions is to limit PGE(2) production in AECs after injury, thus promoting fibrogenesis.
Moore
Bethany B
BB
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA. Bmoore@umich.edu
Peters-Golden
Marc
M
Christensen
Paul J
PJ
Lama
Vibha
V
Kuziel
William A
WA
Paine
Robert
R
Toews
Galen B
GB
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000494:pharmacology / Q000502:physiology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D011453:Prostaglandins / Q000096:biosynthesis; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000502:physiology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology*
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D011453:Prostaglandins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D015232:Dinoprostone