The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production, in vivo

Strassmann, Gideon; Fong, Miranda; Windsor, S; Neta, Ruth

doi:10.1016/1043-4666(93)90058-d

Cited by 69 publications

(52 citation statements)

References 17 publications

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“…Even when administered locally, soluble anti-CD40 caused a substantial weight loss in treated mice for several days following the initiation of therapy, which was statistically significant (versus PBS-injected controls) on days 2-6 after the start of therapy. The weight loss peaked at ~10% on day 3, comparable to the loss experienced by mice in an inflammatory lipopolysaccharide (LPS)-induced acute phase response [67,68]. This result is consistent with the expectation that soluble anti-CD40 can drain rapidly from the injection site, enter the systemic circulation, and cause widespread inflammatory effects.…”

Section: Anti-tumor Efficacy and Systemic Toxicity Following Intratumsupporting

confidence: 75%

Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

2011

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Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bio-activity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immunoagonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpGliposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40+CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally administered soluble immunotherapy, anti-CD40/CpG liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation.

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Section: Anti-tumor Efficacy and Systemic Toxicity Following Intratumsupporting

confidence: 75%

Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

2011

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“…Proinflammatory cytokines such as IL-6 have been implicated in numerous models of cachexia, including the Col26 model (Strassmann et al, 1993;Soda et al, 1995a,b), and cachexia has been at least partially inhibited/reversed with a neutralizing IL-6 antibody in this model (Fujita et al, 1996). We observed that both celecoxib and indomethacin stabilized circulating IL-6 levels, whereas vehicle-treated animals went from 189 to 289 pg/ml (P Ͻ 0.05) during the 4-day study (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Cyclooxygenase-2 by Celecoxib Reverses Tumor-Induced Wasting

Davis¹,

Zweifel²,

O’Neal³

et al. 2004

J Pharmacol Exp Ther

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There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia.Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.

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“…Whether this attenuation occurred directly due to VWR or to attenuation in inflammation is not known. Ellingsgaard et al (9) recently demonstrated that an acute injection of IL-6 induces increases in insulin secretion, and IL-6 is known to have a part in regulation of glucose homeostasis in response to LPS (33). Therefore, it is possible that attenuated insulin resistance at 6 h post-LPS occurs secondary to alterations in inflammatory levels.…”

Section: R938 Wheel Running Attenuates Lps-induced Liver Inflammationmentioning

confidence: 99%

Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice

Peppler

Anderson

Sutton

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Peppler WT, Anderson ZG, Sutton CD, Rector RS, Wright DC. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice. Am J Physiol Regul Integr Comp Physiol 310: R934 -R942, 2016. First published February 17, 2016 doi:10.1152/ajpregu.00497.2015.-Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n ϭ 80, ϳ8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P Ͻ 0.05). VWR attenuated increases in LPS-induced IL-6 signaling and mRNA expression of other inflammatory markers (TNF-␣, chemokine C-C motif ligand 2, inducible nitric oxide synthase, IL-10, IL-1␤) in the liver; however, this was not reflected at the whole body level, as systemic markers of inflammation were similar between SED and VWR. Insulin tolerance was greater in VWR compared with SED at 6 but not 12 h after LPS. The protective effect of VWR occurred in parallel with increases in the liver protein content of HSP70/72, a molecular chaperone that can protect against inflammatory challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72. lipopolysaccharide; inflammation; liver; physical activity; exercise SEPSIS IS A CONTINUUM OF CLINICAL events defined by the presence of infection and systemic inflammation (18). The worldwide incidence of sepsis was recently estimated at 437 cases per 100,000 person years between 2003 and 2015, with an associated fatality rate of 17% (11). This puts a significant burden on the health care system, and in the United States alone, the direct hospital costs associated with sepsis are over $24 billion (17).The infiltration of a host with both gram-negative and gram-positive bacterial species is often considered to be the cause of acute sepsis (34). LPS from Escherichia coli, a component of gram-negative bacteria, is often used to produce these effects in rodent models. Upon exposure to LPS, an inflammatory cascade is activated both systemically and at a tissue-specific level (1). Initial signaling involves a Toll-like receptor 4 (TLR4)-myeloid differentiation primary response gene 88 (MyD88) interaction that then propagates the inflammatory response (24). Increases in circulating inflammatory factors, such as TNF-␣, IL-6, and IL-1␤, occur rapidly and are regulated by the dose and duration of exposure (21,29,40). Clearance of inflammatory markers begins as early as 8 h post...

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The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production, in vivo

Cited by 69 publications

References 17 publications

Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

Inhibition of Cyclooxygenase-2 by Celecoxib Reverses Tumor-Induced Wasting

Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice

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