Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis.
The purpose of this study was to determine whether or not membrane-bound and soluble forms of IL-4 receptors are expressed by isolated subsets of murine lung fibroblasts and to evaluate the potential functional consequences of IL-4 receptor triggering. Recent studies demonstrate that IL-4-synthesizing Th2 cells and mast cells are present in increased numbers in the lung during inflammation and fibrosis, suggesting that IL-4 may play a regulatory role in these events. We hypothesize that pulmonary fibroblasts and subsets thereof are intimately involved in this inflammatory response and that IL-4 is an active player in stimulating fibroblast collagen synthesis and hyperproliferation, creating a fibrotic environment in the lung. The fibroblast subsets used in these experiments differ not only in surface expression of the thymocyte-1 (Thy-1) Ag, but also in function and morphology. We now report the novel finding that IL-4 receptors are present at discordant levels on Thy-1+ and Thy-1- lung fibroblasts. IL-4R level and affinity were analyzed using a monoclonal anti-IL-4R Ab and equilibrium binding analysis with 125I-labeled IL-4. Reverse transcriptase PCR demonstrated the presence of mRNA for membrane-bound and soluble IL-4R. Lung fibroblast subsets secrete soluble IL-4R protein at dramatically different levels, as detected by an ELISA. Thy-1+ and Thy-1- lung fibroblasts were treated with IL-4 to determine whether this cytokine was profibrotic. Thy-1+ fibroblasts responded to IL-4 by proliferating and up-regulating collagen production. In contrast, Thy-1- fibroblasts proliferate to a lesser degree than Thy-1+ fibroblasts and were not stimulated to secrete increased levels of collagen. Overall, these results suggest that elevated levels of IL-4 at a site of injury could result in the development of fibrosis by enhancing fibroblast subset proliferation and collagen synthesis.
Sempowski
G D
GD
University of Rochester Cancer Center, University of Rochester School of Medicine and Dentistry, NY 14642.
Beckmann
M P
MP
Derdak
S
S
Phipps
R P
RP
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis*; D017931:DNA Primers / Q000737:chemistry; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D018800:Thy-1 Antigens
D000954:Antigens, Surface; D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D018800:Thy-1 Antigens; D015847:Interleukin-4; D003094:Collagen