Macrophage migration inflammatory factor (MIF) functions in inflammatory responses, and one mechanism for its proinflammatory activity is as a chemoattractant for monocytes through the binding of MIF to the chemokine receptors CXCR2 and CXCR4. In addition to binding to chemokine receptors, MIF also binds CD74 (a protein that colocalizes with CXCR2). Filip et al. sought to identify regulators of MIF activity and found through two independent methods that ribosomal protein S19 (RPS19) interacted with MIF. Further biochemical characterization showed that the interaction was direct. Immunofluorescence experiments indicated that the two endogenous proteins colocalized in a cultured cell line. MIF has enzymatic activity, acting as a tautomerase and oxidoreductase. However, addition of RPS19 to MIF in a tautomerization assay only moderately decreased this enzymatic activity of MIF. In an enzyme-linked immunosorbent assay, RPS19 reduced MIF binding to CD74 by ~50%, and, in a flow chamber adhesion assay, RPS19 decreased the adhesion of monocytes to human aortic endothelial cells treated with MIF. The authors suggest that when cells die, they release RPS19, which inhibits the extracellular proinflammatory activity of MIF by decreasing its binding to the chemokine receptors and CD74.
A.-M. Filip, J. Klug, S. Cayli, S. Fröhlich, T. Henke, P. Lacher, R. Eickhoff, P. Bulau, M. Linder, C. Carlsson-Skwirut, L. Leng, R. Bucala, S. Kraemer, J. Bernhagen, A. Meinhardt, Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function. J. Biol. Chem. 284, 7977–7985 (2009). [Abstract] [Full Text]