Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN
| Autor: | Stefan Rose-John, Oliver M. Steinmetz, Michael Luig, Anna Nosko, Malte A. Kluger, Boeren Goerke, Jürgen Scheller, Isabell Yan, Ulf Panzer, Hans-Willi Mittrücker, Rolf A.K. Stahl, Matthias C. Meyer |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Inflammation Real-Time Polymerase Chain Reaction Sensitivity and Specificity Proinflammatory cytokine Mice Random Allocation Glomerulonephritis Immune system Up Front Matters medicine Animals Macrophage Interleukin 6 Cells Cultured Cell Proliferation Mice Knockout Analysis of Variance biology Interleukin-6 Macrophages General Medicine Flow Cytometry Glycoprotein 130 medicine.disease Immunohistochemistry Receptors Interleukin-6 Mice Inbred C57BL Disease Models Animal Basic Research Nephrology Immunology biology.protein medicine.symptom Macrophage proliferation Nephritis Signal Transduction |
| Zdroj: | Journal of the American Society of Nephrology. 26:1597-1607 |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/asn.2014060620 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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