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  • Title: Melanoma inhibits macrophage activation by suppressing toll-like receptor 4 signaling.
    Author: Clarke JH, Cha JY, Walsh MD, Gamboni-Robertson F, Banerjee A, Reznikov LL, Dinarello CA, Harken AH, McCarter MD.
    Journal: J Am Coll Surg; 2005 Sep; 201(3):418-25. PubMed ID: 16125076.
    Abstract:
    BACKGROUND: Activated macrophages defend against tumors by secreting cytokines to recruit secondary immune cells, presenting antigen to T cells, and by direct tumor cytotoxicity. Peritoneal macrophages harvested from melanoma-bearing mice are less cytotoxic to melanoma cells, and produce less superoxide, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha) than those from nontumor-bearing mice. Similar impairment of macrophage activation occurs in vitro using media harvested from cultured melanoma cells. Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. We hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling. STUDY DESIGN: Melanoma conditioned media (MCM) was generated from B16 melanoma cells. Peritoneal macrophages from TLR-4 competent or TLR-4 incompetent mice were exposed to control or MCM for 24 hours; then stimulated with lipopolysaccharide. TNF-alpha secretion, TNF-alpha mRNA production, nuclear factor-kappaB (NF-kappaB) activation, and TLR-4 surface expression were measured. RESULTS: Peritoneal macrophages exposed to MCM produced considerably less TNF-alpha in response to stimulus than controls (691 pg/mL versus 2,066 pg/mL, p < 0.001). TNF-alpha production by TLR-4 incompetent macrophages was not affected by MCM (454 pg/mL versus 480 pg/mL). Stimulated TNF-alpha mRNA and activated NF-kappaB were decreased in MCM treated C57BL/6 macrophages (by 38% and 33%, respectively). TLR-4 surface expression, however, was not decreased by exposure to MCM. CONCLUSIONS: Melanoma inhibits macrophage activation by suppressing TLR-4 signaling downstream of the TLR-4 receptor.
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