title: MIF inhibits monocytic movement through a non-canonical receptor and disruption of temporal Rho GTPase activities in U-937 cells.
abstract: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that was initially identified by its ability to inhibit the movement of macrophages. Cell migration is a highly complex process involving changes to the cytoskeleton and cell adhesion molecules, and is regulated by the Rho GTPases. A simple model using human monocytic U-937 cells to elicit the classic MIF response was implemented to examine the mechanism of MIF-induced migration inhibition. Our results demonstrate that MIF inhibits migration of these U-937 cells through a non-canonical receptor, CXCR4, in the absence of the putative primary MIF receptor CD74. Migration inhibition is dependent upon a series of temporal perturbations of the activities of the Rho GTPases: initial activation followed by subsequent inactivation of RhoA, inactivation of Rac1, and cyclic activation of Cdc42. MIF-mediated changes in the activities of the Rho GTPases jointly contributed to migration inhibition in these cells. Collectively, these data suggest that the MIF-mediated migration inhibition is mediated by the outcome of G-protein signaling, and in less adherent cells such as those of the monocyte/macrophage lineage, RhoA directly affects net translocation through its ability to induce cell body contraction. These findings demonstrate that CXCR4 can mediate MIF signaling in the absence of CD74 in addition to serving as a MIF co-receptor along with CD74. These results correlate MIF activity to specific and sequential Rho GTPase activity perturbations, and given that CXCR4 functions in numerous processes, suggests potential roles for the modulation of cell movement in those events including development, cell survival and viral infection.
authors.affiliation: Program in Molecular Pathology and Immunology, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States. Electronic address: c_dicosmo@hotmail.com.
authors.forename: Crystal J
authors.initials: CJ
authors.lastname: DiCosmo-Ponticello
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States. Electronic address: danieljohnhoover@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoover
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Biophysical Pathology, Rutgers New Jersey Medical School, Newark, NJ 07101, United States. Electronic address: coffmafd@njms.rutgers.edu.
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Coffman
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Biophysical Pathology, Rutgers New Jersey Medical School, Newark, NJ 07101, United States. Electronic address: cohenst@njms.rutgers.edu.
authors.forename: Stanley
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Rutgers Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07101, United States; Department of Pathology, SUNY Downstate Med. Ctr., Brooklyn, NY, United States. Electronic address: cohenmarion@verizon.net.
authors.forename: Marion C
authors.initials: MC
authors.lastname: Cohen
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism; D057809:HEK293 Cells; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D010750:Phosphoproteins / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction; D020298:U937 Cells; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C514543:ARHGAP31 protein, human; D000944:Antigens, Differentiation, B-Lymphocyte; C527276:CXCR4 protein, human; D015815:Cell Adhesion Molecules; D020690:GTPase-Activating Proteins; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D010750:Phosphoproteins; C107953:RAC1 protein, human; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; C045084:invariant chain; C066737:RHOA protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: CXCR4; Migration inhibitory factor; Rho GTPases; U937