In this report we describe an experimental model of cachexia that fulfills the criteria of an early effect with a small tumor mass not related to the growth rate of the tumor, and progressive wasting of muscle and fat without a detectable loss of appetite. C-26.IVX is a cell line derived from murine colon-26 adenocarcinoma which retains the transplantability of the original tumor and induces true cachexia in syngeneic hosts. Evidence is presented to support a role for interleukin (IL-6) as a cachectic factor in the development of cancer cachexia in this model system. Thus, increasing levels of IL-6 in C-26.IVX-bearing mice correlate with the development of cachexia. If the primary tumors were resected, mice gained weight and the levels ofIL-6 in the serum were reduced significantly. Moreover, monoclonal antibody to murine IL-6 (but not anti-tumor necrosis factor antibody) was able to significantly suppress the development of key parameters of cachexia in tumor bearing mice. (J. Clin.

SummaryAmong other effects, prostaglandins (PG) of the E series are known to inhibit several acute and chronic inflammatory conditions in vivo and proinflammatory cytokine production by activated macrophages in culture. The research presented here demonstrates that the inhibitory effect of PGE2 on tumor necrosis factor oe (TNF-oL) and interleukin 6 (IL-6) production by lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages involves IL-10. In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-ol and IL-6, but not of lactate or nitric oxide. The decrease in the level of these cytokines is inversely proportional to the increase in immunoreactive IL-10. This differential inhibitory effect of PGE2 is mimicked by agents that elevate intracellular levels of cAMP, but not cGMP. Neutralizing anti IL-10 antibody but not neutralizing antibodies against other macrophage secretory products (IL-6, leukemia inhibitory factor, and transforming growth factor fl [TGF-fl]), significantly reverse the potent inhibitory effect of PGE2. In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-cr and IL-6 levels. Anti-IL-10 antibody substantially enhanced the LPS-induced TNF-o~ and IL-6 levels in mice that received either LPS alone or LPS plus PGE2. These results suggest that the antiinflammatory effect of PGE2 on mononuclear phagocytes is mediated in part by an autocrine feedback mechanism involving IL-10.M ononuclear phagocytes (macrophages) play a central role in the regulation of immune responses as well as in both acute and chronic inflammation. The mechanisms that participate in these activities are believed to be multifactorial and involve macrophage secretory products (for a review see reference 1). TNF-ol is an important macrophage inflammatory cytokine that mediates a wide range of biologic functions. TNF-c~ is believed to play a major role in septic shock, and to contribute to the pathogenesis of AIDS and several inflammatory and autoimmune diseases (for reviews see references 2, 3). Recently, a number of regulatory factors were described as having the capacity to block macrophage functions, including TNF-cr release. These molecules, also termed "macrophage-deactivating factors;' include PG of the E series (4-8), TGF-3 (9), IL-4 (10), and 12). In addition to their capacity to induce pain, vascular changes and downregulation of T cell functions, PG have been shown to exhibit antiinflammatory properties on macrophages. For example, stimulation of macrophages by LPS or by TNF-c~ induces PGE2 production (13,14), and the addition of PGE2 to LPS-stimulated cells inhibits TNF-c~ mRNA expression and protein secretion (6-8). This information leads to the hypothesis that the release of PG during LPS-induced inflammation constitutes a negative-feedback mechanism that limits the magnitude of inflammatory cytokine production. In vivo, the exogenous administration of PGE suppresses adjuvant arthritis in rats (15), inhibits the manifestation of interstitial nephritis (16), and...

The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.

Isolation and characterization of a distinct cytokine pattern in patients with advanced cancer treated with AS101 may contribute to the development of intervention strategies using this compound.

Neoplastic diseases are frequently associated with metabolic changes collectively known as cancer cachexia. The presence of cachexia complicates therapeutic intervention and is an important cause of death in cancer patients. At present there is no effective treatment for cachexia. Recently, the involvement of interleukin-6 (IL-6) in the wasting of colon-26 adenocarcinoma-bearing mice was demonstrated. The research presented here establishes an anticachectic role for the experimental drug suramin, since it partially blocks (up to 60%) the catabolic effects associated with the growth of this tumor in vivo. Suramin prevents the binding of IL-6 to its cell surface receptor subunits, as demonstrated by radioreceptor binding assay and affinity crosslinking experiments. Furthermore, the uptake of radioactive IL-6 by the liver is significantly reduced in suramintreated mice. On the other hand, the drug is 10-fold less potent in inhibiting the binding of tumor necrosis factor-a to indicator cell line in vitro and fails to block liver uptake of this cytokine in vivo. Collectively, these results suggest that suramin inhibits cancer-associated wasting, in part by interfering with the binding of IL-6 to its receptor. Whether suramin inhibits the action ofother factors /cytokines that may also participate in colon-26-mediated cachexia is not yet known. (J. Clin.