Limited involvement of interleukin‐6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin‐6 or its receptor in various murine models

Abstract

Several studies in human patients and in laboratory animals have revealed a correlation between serum interleukin (IL)-6 levels and outcome in clinical sepsis and in related animal models, respectively. In the present study, two monoclonal antibodies were used to investigate the contribution of IL-6 in the lethal action of tumor necrosis factor (TNF) and of lipopolysaccharide (LPS) in mice. We studied the potential protective properties of an anti-murine (m) IL-6 antibody and of an anti-mIL-6 receptor antibody. In controlled experiments, we observed that both monoclonal antibodies conferred a dose-dependent protection to a lethal dose of mTNF. Detailed studies with the monoclonal antibodies indicate, however, that protection was no longer observed when the mTNF dose was slightly higher than the lethal dose. Likewise, the anti-IL-6 monoclonal antibody protected against injections of LPS at a lethal-dose concentration, but here too failed to protect against higher doses of LPS. The anti-IL-6 monoclonal antibody was unable to protect against mTNF in mice sensitized by galactosamine, the corticoid receptor antagonist RU38486 or human (h) IL-1 beta. Protection did not correlate with the serum concentrations of IL-6. Finally, we demonstrate that hIL-6 injection did not change the sensitivity of mice towards mTNF. We conclude that, although IL-6 levels may be of value as a marker for the outcome in septic shock, this cytokine contributes only marginally in the pathogenesis leading to death. The small, but real, contribution of IL-6 in some situations might be due to its ability to up-regulate the level of TNF receptors.

Interleukin-6 Deficiency Increases Inflammatory Bone Destruction

“…Infusion of IL-6 in humans results in fever but does not cause shock or a capillary leakage syndrome as is observed with proinflammatory cytokines such as IL-1␤ and TNF (26). This is also the case in animal models (3).…”

Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation.

“…Transgenic animals were identified by PCR analysis of DNA extracted from a tail segment, as described (18 1985). To evaluate the effect of the inhibition of hIL-6 action, NSE/hIL-6 mice were injected subcutaneously at days 2, 4, 7, 11, 14, and 20 after birth (day 0) with the neutralizing rat monoclonal antibody 15A7 to the murine IL-6 receptor (19) at doses of 90 g/mouse at day 2, 150 g/mouse at day 4, and of 300 g/mouse at day 7 and thereafter. The antibody was pre-cipitated from the hybridoma cell medium in saturating ammonium sulphate, dialyzed against 50 mM Tris/HCl, pH 7.5, and loaded on a protein G-Sepharose resin (cat.…”

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

“…For local blockade of TGF-b, mouse anti-TGF-b1, 2, and 3 IgG1 (clone 1D11; 100 mg/50 ml PBS) were pharyngeally injected also at days 21 and +1. The Abs were purified according to standard procedures, and all dosing regimens were previously found to be sufficient for neutralization of IL-17A (20)(21)(22), IL-23p40 (23), CD4 (24), IL-6/IL-6R (25), and TGF-b (26). IgG isotype controls were mouse anti-trinitrophenyl IgG1 (B9603D11), mouse anti-keyhole limpet hemocyanin IgG1 (MAB002; clone 11711, R&D Systems), and rat anti-keyhole limpet hemocyanin IgG2a (MAB006; clone 54447, R&D Systems).…”