No abstract

C57BL/6J mice given low doses of lipopolysaccharide (LPS) (100 ng per mouse) plus D-galactosamine (8 mg per mouse) die within 24 h following LPS administration. We used this septic shock model to confirm the role of tumor necrosis factor in mortality using a monoclonal antibody to tumor necrosis factor to prevent lethality. Furthermore, we demonstrated that interleukin 6, rather than playing a lethal role, protected mice against death in this septic shock model. Antibody to interleukin 6 did not affect the fatal outcome in this low-LPS-dose model. However, pretreatment with antibody to tumor necrosis factor did protect the mice against death, in a dose-dependent manner. Moreover, mortality was enhanced by pretreatment with antibody to interleukin 6 when tumor necrosis factor was partly limited by anti-tumor necrosis factor treatment. Mortality was significantly reduced by pretreatment with both recombinant interleukin 6 and low doses of antibody to tumor necrosis factor; in the absence of the low dose of antibody to tumor necrosis factor, interleukin 6 alone did not confer any protection. These data demonstrate in vivo antagonistic activities of tumor necrosis factor and interleukin 6 and show that interleukin 6 can play a protective role against death from septic shock.

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An estimated 30% of cancer deaths are attributed to cachexia and its consequences. Cachexia (wasting syndrome) is the hypercatabolism of the body's carbon sources, proteins and lipids, for conversion into energy. It is induced by a variety of pathological conditions, including cancer. Among the inflammatory responses to cancer is the synthesis of cytokines, including IL-6 and related cytokines. These cytokines have been found to induce cachexia by altering metabolism of lipids and proteins. IL-6-like cytokines have been found to inhibit lipid biosynthesis by adipocytes, which increased the rate of lipid catabolism. Others have described the atrophy and increased catabolism of muscle protein due to IL-6. A cytokine closely-related to IL-6 is leptin, which plays a major role in lipid metabolism under normal conditions. The role of leptin in pathological conditions such as cancer cachexia has not yet been fully elucidated. Detailed mechanistic information about the induction of cancer cachexia by IL-6-like cytokines requires more research.

Interleukin-6 (IL-6) is a pleiomorphic cytokine whose growth factor properties play an important role in the development and progression of many types of cancer. IL-6 is produced in response to a variety of stimuli, and is required for the development of T and B lymphocytes to effector cells. In certain neoplasias, such as multiple myeloma, IL-6 is both produced and required for survival by the cancer cell itself. In other neoplasias, IL-6 may come from tissue surrounding the tumour. Thus, therapeutic strategies aimed at inhibiting the production, expression or action of IL-6 would be quite beneficial in the treatment of cancer. Moreover, IL-6 is a pathophysiological factor in several hyperproliferative diseases and the paraneoplastic syndromes that often accompany cancer, such as cachexia and osteoporosis; thus, anti-IL-6 therapy would be useful in treating these entities as well. This expert opinion acquaints the reader with IL-6, its physiological responses, the cancer types with which it is associated, and discusses the current state of therapy aimed at inhibiting it.