LABORATORY INVESTIGATIONS

Pathogenic role of interleukin-6 in the development of sepsis. Part II: Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-α antibodies in a standardized murine contact burn model

Pallua, Norbert MD, PhD; Low, Janina F. A. MD; von Heimburg, Dennis MD, PhD

From the Department of Plastic Surgery and Hand Surgery–Burn Center, University Hospital of the Aachen University of Technology, Aachen, Germany.

Address requests for reprints to: N. Pallua, MD, PhD, Professor and Chairman, Department of Plastic Surgery and Hand Surgery–Burn Center, University Hospital of the Aachen University of Technology, Pauwelsstr. 30, D-52057 Aachen, Germany.

The study suggests that the use of antibodies against interleukin-6 or interleukin-6R is effective in the prevention of systemic inflammation in a murine burn model.

Critical Care Medicine 31(5):p 1495-1501, May 2003. | DOI: 10.1097/01.CCM.0000065725.80882.BD

Abstract

Objective

The in vivo effects of anti-interleukin-6 (anti-IL-6) and anti-interleukin-6-α receptor (anti-IL-6R) monoclonal antibodies on immune response and survival rate of a burn with subsequent infection were assessed.

Subjects

Ten-week-old C 57 BL/6J mice received a standardized contact burn; 48 hrs later endotoxin (LPS) was injected intraperitoneally to induce systemic inflammation. Ten different groups were studied. Groups I–IV sustained a burn and/or a LPS-stimulus but did not receive any anti-cytokines and served as controls. Treatment groups V–X sustained the same injuries but also received anti-IL-6 and anti-IL-6R intravenously either before or after the LPS stimulus. In a further part of the study, a lethal dose of LPS was injected (LPS-LD₁₀₀ group) followed by an injection of anti-IL-6 antibody and/or anti-IL-6R antibody.

Measurements

Serum concentrations of IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and white blood cell and platelet counts were determined, and the survival rate over a 2-wk period was assessed.

Results

Treatment with anti-IL-6 slightly decreased the inflammatory response when it was given before or after LPS application. The inflammatory response was not decreased after treatment with anti-IL-6R. In the groups that received a combination of anti-IL-6 and anti-IL-6R, there was a significant reduction of the inflammatory response. This was more pronounced when the anti-cytokines were applied after LPS application. A significant reduction in mortality could be shown with both antibodies in the treatment groups and the groups that had received a lethal dose of LPS (LPS-LD₁₀₀ group).

Conclusions

IL-6 has a low inflammatory potential, and IL-6R has no inflammatory potential by itself. In contrast, the IL-6/IL-6R complexes have a higher inflammatory potential. Mortality could be reduced by each antibody alone as well as by the combination, supporting the hypothesis that the inflammatory and lethal potentials of IL-6 are not identical. The study suggests that the use of antibodies against IL-6 or IL-6R is effective in the prevention of systemic inflammation in a murine burn model.