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J Immunol. 2018 May 15;200(10):3547-3555. doi: 10.4049/jimmunol.1701191. Epub 2018 Apr 6.

Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130.

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Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
School of Medicine, University of Queensland, Herston, Queensland 4006, Australia; and.
Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia;


IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Rα or soluble IL-6Rα. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p-STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex. Furthermore, we demonstrate that this is due to a lack of gp130 expression on mouse and human granulocytes, despite their expression of membrane-bound IL-6R. Importantly, the absence of gp130 is not only a feature of mature granulocytes in healthy individuals, it is also observed after allogeneic stem cell transplantation. Moreover, granulocyte gp130 expression is lost during maturation, because granulocyte-monocyte progenitor cells express gp130 and respond to IL-6. Given that granulocytes constitute 50-70% of circulating leukocytes, this indicates a significantly smaller scope of IL-6 signaling than previously anticipated and has important implications for therapeutic IL-6 inhibition and the mechanisms of action thereof.

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