title: Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function.
abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in the pathogenesis of inflammatory disorders such as infection, sepsis, and autoimmune disease. MIF exists preformed in cytoplasmic pools and exhibits an intrinsic tautomerase and oxidoreductase activity. MIF levels are elevated in the serum of animals and patients with infection or different inflammatory disorders. To elucidate how MIF actions are controlled, we searched for endogenous MIF-interacting proteins with the potential to interfere with key MIF functions. Using in vivo biotin-tagging and endogenous co-immunoprecipitation, the ribosomal protein S19 (RPS19) was identified as a novel MIF binding partner. Surface plasmon resonance and pulldown experiments with wild type and mutant MIF revealed a direct physical interaction of the two proteins (K(D) = 1.3 x 10(-6) m). As RPS19 is released in inflammatory lesions by apoptotic cells, we explored whether it affects MIF function and inhibits its binding to receptors CD74 and CXCR2. Low doses of RPS19 were found to strongly inhibit MIF-CD74 interaction. Furthermore, RPS19 significantly compromised CXCR2-dependent MIF-triggered adhesion of monocytes to endothelial cells under flow conditions. We, therefore, propose that RPS19 acts as an extracellular negative regulator of MIF.
authors.affiliation: Department of Anatomy and Cell Biology, Unit of Reproductive Biology, Medical Clinic II, and Department of Biochemistry, Justus-Liebig-University of Giessen, Giessen D-35385, Germany.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Filip
authors.forename: Jörg
authors.initials: J
authors.lastname: Klug
authors.forename: Sevil
authors.initials: S
authors.lastname: Cayli
authors.forename: Suada
authors.initials: S
authors.lastname: Fröhlich
authors.forename: Tamara
authors.initials: T
authors.lastname: Henke
authors.forename: Philipp
authors.initials: P
authors.lastname: Lacher
authors.forename: Regina
authors.initials: R
authors.lastname: Eickhoff
authors.forename: Patrick
authors.initials: P
authors.lastname: Bulau
authors.forename: Monika
authors.initials: M
authors.lastname: Linder
authors.forename: Christine
authors.initials: C
authors.lastname: Carlsson-Skwirut
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Sandra
authors.initials: S
authors.lastname: Kraemer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D041681:NIH 3T3 Cells; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D023063:Receptors, Interleukin-8B; D012269:Ribosomal Proteins; C040343:ribosomal protein S19; D010088:Oxidoreductases