title: Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN.
abstract: IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.
authors: Medical Clinic III and.
authors: Michael
authors: M
authors: Luig
authors: Medical Clinic III and.
authors: Malte A
authors: MA
authors: Kluger
authors: Medical Clinic III and.
authors: Boeren
authors: B
authors: Goerke
authors: Medical Clinic III and.
authors: Matthias
authors: M
authors: Meyer
authors: Medical Clinic III and.
authors: Anna
authors: A
authors: Nosko
authors: Immunology Institute, Hamburg University Medical Center, Hamburg, Germany;
authors: Isabell
authors: I
authors: Yan
authors: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; and.
authors: Jürgen
authors: J
authors: Scheller
authors: Immunology Institute, Hamburg University Medical Center, Hamburg, Germany;
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors: Stefan
authors: S
authors: Rose-John
authors: Medical Clinic III and.
authors: Rolf A K
authors: RA
authors: Stahl
authors: Medical Clinic III and.
authors: Ulf
authors: U
authors: Panzer
authors: Medical Clinic III and o.steinmetz@uke.de.
authors: Oliver M
authors: OM
authors: Steinmetz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: GN; cytokines; immunology; pathology
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