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.
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.


METHODS
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.


METHODS
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.
Pallua
Norbert
N
Department of Plastic Surgery and Hand Surgery--Burn Center, University Hospital of the Aachen University of Technology, Germany.
Low
Janina F A
JF
von Heimburg
Dennis
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002056:Burns / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D007249:Inflammation; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D011552:Pseudomonas Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D011897:Random Allocation; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D007371:Interferon-gamma; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C113250:interleukin-6 receptor alpha