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

Abstract

OBJECTIVE:

The in vivo effects of anti-interleukin-6 (anti-IL-6) and anti-interleukin-6-alpha 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-LD(100) 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)-alpha, interferon (IFN)-gamma, 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-LD(100) 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.

• Authors: Norbert Pallua, Janina F A Low, Dennis von Heimburg
• Journal: Critical care medicine (Crit Care Med) Vol. 31 Issue 5 Pg. 1495-501 (May 2003) ISSN: 0090-3493 [Print] United States
• PMID: 12771624 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Interleukin-6
• Receptors, Interleukin-6
• Tumor Necrosis Factor-alpha
• interleukin-6 receptor alpha
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Burns (blood, complications, drug therapy, immunology, mortality)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Therapy, Combination
• Inflammation
• Interferon-gamma (blood)
• Interleukin-6 (antagonists & inhibitors, blood, immunology)
• Leukocyte Count
• Male
• Mice
• Mice, Inbred C57BL
• Platelet Count
• Pseudomonas Infections (blood, complications, drug therapy, immunology, mortality)
• Random Allocation
• Receptors, Interleukin-6 (antagonists & inhibitors, immunology)
• Survival Analysis
• Systemic Inflammatory Response Syndrome (blood, drug therapy, etiology, immunology, mortality)
• Time Factors
• Treatment Outcome
• Tumor Necrosis Factor-alpha (metabolism)