title: Surface expression of CD74 by type II alveolar epithelial cells: a potential mechanism for macrophage migration inhibitory factor-induced epithelial repair.
abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine involved in acute lung injury and other processes such as wound repair and tumor growth. MIF exerts pro-proliferative effects on a variety of cell types including monocytes/macrophages, B cells, and gastric epithelial cell lines through binding to the major histocompatibility complex type II-associated invariant chain, CD74. In acute lung injury, inflammatory damage of the alveolar epithelium leads to loss of type I alveolar epithelial cells (AEC-I), which are replaced by proliferation and differentiation of type II alveolar epithelial cells (AEC-II). In this study we have investigated the potential of MIF to contribute to alveolar repair by stimulating alveolar epithelial cell proliferation. We show that murine AEC-II, but not AEC-I, express high surface levels of CD74 in vivo. Culture of AEC-II in vitro resulted in decreased mRNA levels for CD74 and loss of surface CD74 expression, which correlated with a transition of AEC-II to an AEC-I-like phenotype. MIF stimulation of AEC-II induced rapid and prolonged phosphorylation of ERK1/2 and Akt, increased expression of cyclins D1 and E, as well as AEC-II proliferation. Corresponding MIF signaling and enhanced thymidine incorporation was observed after MIF stimulation of MLE-12 cells transfected to overexpress CD74. In contrast, MIF did not induce MAPK activation, gene transcription, or increased proliferation in differentiated AEC-I-like cells that lack CD74. These data suggest a previously unidentified role of MIF-CD74 interaction by inducing proliferation of AEC-II, which may contribute to alveolar repair.
authors.affiliation: Department of Internal Medicine, Giessen and Marburg University, University Giessen Lung Centre, Giessen, Germany. leigh.marsh@uglc.de
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.forename: Lidija
authors.initials: L
authors.lastname: Cakarova
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.forename: Werner
authors.initials: W
authors.lastname: von Wulffen
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Juergen
authors.initials: J
authors.lastname: Lohmeyer
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000145:classification / Q000166:cytology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000276:immunology*; D037721:Pulmonary Surfactant-Associated Protein C; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; C045084:invariant chain