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Departments of
*
Pathology and
Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Pathology, Veteran Affairs Medical Center, Ann Arbor, MI 48105
Recent studies suggest that monocyte chemoattractant protein-1
(MCP-1) is involved in fibrosis through the regulation of profibrotic
cytokine generation and matrix deposition. Changes in MCP-1, C-C
chemokine receptor 2 (CCR2), procollagen I and III, and TGF ß were
examined in fibroblasts cultured from normal lung and from nonfibrotic
(i.e., Th1-type) and fibrotic (i.e., Th2-type) pulmonary granulomas.
Th2-type fibroblasts generated 2-fold more MCP-1 than similar numbers
of Th1-type or normal fibroblasts after 24 h in culture. Unlike
normal and Th1-type fibroblasts, Th2-type fibroblasts displayed CCR2
mRNA at 24 h after IL-4 treatment. By flow cytometry, CCR2 was
present on 40% of untreated Th2-type fibroblasts, whereas CCR2 was
present on <20% of normal and Th1-type fibroblasts after similar
treatment. IL-4 increased the number of normal fibroblasts with
cell-surface CCR2 but IFN-
-treatment of normal and Th2-type
fibroblasts significantly decreased the numbers of CCR2-positive cells
in both populations. Western blot analysis showed that total CCR2
protein expression was markedly increased in untreated Th2-type
fibroblasts compared with normal and Th1-type fibroblasts. IL-4
treatment enhanced CCR2 protein in Th1- and Th2-type fibroblasts
whereas IFN- treatment augmented CCR2 protein in normal and Th1-type
fibroblasts. All three fibroblast populations exhibited MCP-1-dependent
TGF-ß synthesis, but only normal and Th2-type fibroblasts showed a
MCP-1 requirement for procollagen mRNA expression. Taken together,
these findings suggest that lung fibroblasts are altered in their
expression of MCP-1, TGF-ß, CCR2, and procollagen following their
participation in pulmonary inflammatory processes, and these changes
may be important during fibrosis.
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