IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Abstract

The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6–mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6Rα (mIL-6Rα) and gp130. Owing to the restricted expression of mIL-6Rα, classical IL-6 signaling occurs only in a limited number of cells such as hepatocytes and certain leukocyte subsets. IL-6 also interacts with soluble IL-6Rα proteins and these IL-6/soluble IL-6Rα complexes can subsequently bind to membrane-bound gp130 proteins and induce signaling. Because gp130 is ubiquitously expressed, this IL-6 trans-signaling substantially increases the spectrum of cells responding to IL-6. In this study, we analyze the role of classical IL-6 signaling and IL-6 trans-signaling in the innate immune response of mice against Listeria monocytogenes infection. We demonstrate that L. monocytogenes infection causes profound systemic IL-6 production and rapid loss of IL-6Rα surface expression on neutrophils, inflammatory monocytes, and different lymphocyte subsets. IL-6–deficient mice or mice treated with neutralizing anti–IL-6 mAb displayed impaired control of L. monocytogenes infection accompanied by alterations in the expression of inflammatory cytokines and chemokines, as well as in the recruitment of inflammatory cells. In contrast, restricted blockade of IL-6 trans-signaling by application or transgenic expression of a soluble gp130 protein did not restrain the control of infection. In summary, our results demonstrate that IL-6Rα surface expression is highly dynamic during the innate response against L. monocytogenes and that the protective IL-6 function is dependent on classical IL-6 signaling via mIL-6Rα.

Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

“…We showed how targeting site IIb of IL-6R would be favorable to inhibit an exacerbated IL-6-induced response, here measured by SAA induction typically associated with a cis-mediated event (30). The injection of anti-IL-6R mAbs to mice when IL-6 serum levels were maximal showed that 25F10 significantly reduced the IL-6-driven SAA response.…”

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

“…60 Antibodies were applied in doses previously shown to be effective, including anti-IL-6R (750 mg, MR16-1; provided by Chugai Pharmaceutical Co. Ltd., Tokyo, Japan 33 ), anti-IL-6 (500 mg, MP5-20F3), and sgp130Fc (250 mg), 61 or control antibodies (750 mg rat IgG for MR16-1 or 500 mg hIgG for anti-IL-6 and sgp130Fc) were intraperitoneally injected 24 hours before and 5 days after NTN induction. For aNTN, 41 mice were preimmunized with sheep IgG in complete Freund's adjuvant at day 5.…”

The soluble interleukin-6 receptor and related proteins

“…4) [62]. Interestingly we found in animals that the defense of the organism from bacterial infections depends on the membrane bound IL-6R and is not compromised when only IL-6 trans-signaling is blocked [63,64]. This has consequences for the therapeutic blockade of cytokines.…”