Tumour necrosis factor (TNF) as a mediator of macrophage helminthotoxic activity

Abstract

Lymphokine-activated macrophages are cytotoxic for larvae of the helminth parasite Schistosoma mansoni. That soluble secreted factors may mediate this cytotoxicity was suggested by the observation that culture supernatant fluids from stimulated macrophages also exhibited larvacidal activity. These fluids contain the monokine tumour necrosis factor (TNF). Several observations indicated that TNF is directly toxic to schistosome larvae. Cytotoxic sera taken from BCG- or S. mansoni-immunized mice after endotoxin challenge killed schistosomula in vitro, and upon gel filtration the larvacidal factor(s) in the sera co-eluted with the tumoricidal activity defined as TNF. Recombinant-derived TNF exhibited direct toxicity to schistosomula at high concentrations, or at lower concentrations in the presence of IFN gamma. The larvacidal activity of macrophage supernatant fluids was abrogated by addition of either anti-TNF antisera or Zn+2, which has been shown to inhibit TNF-induced damage of tumour cells. Anti-TNF and Zn+2 likewise suppressed schistosomulum killing by lymphokine-activated peritoneal macrophages or the IC-21 macrophage line, indicating that TNF also plays a role in the effector mechanism of larval killing by whole cells.

Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide.

“…ECs appear to be capable of mediating larval killing in a manner analogous to that observed with tissue macrophages (6,11). However, conditions for the participation of ECs in the effector mechanism of CMI to S. mansoni may be more stringent than those stimulating macrophage function, since multiple activating stimuli are apparently required ( Immunology: Oswald et A be stringent (Fig.…”

“…In vitro, interferon fy (IFN-y)-activated murine macrophages kill larval schistosomula through an argininedependent mechanism involving production of reactive nitrogen oxides (6). NO has likewise been implicated as an effector molecule of macrophage-mediated cytotoxicity against tumor cells and multiple protist targets, where it has been shown to interfere with DNA replication, the citric acid cycle, and mitochondrial respiration (7).…”

“…Three-hour schistosomula were mechanically transformed from cercariae (6). Older parasites were recovered by perfusion from the hepatic portal system of mice that were infected 18 days before by percutaneous exposure to 3 x 103 cercaria (5).…”

“…For larvicidal assays (6,11), ECs or macrophages were cultured with newly transformed schistosomula or 2.5-week-old parasites for 48 or 72 hr, respectively, at effector/target ratios varying from 0.5 x 104:1 to 2 x 104:1 in complete medium. Larval killing was determined microscopically by the criteria of internal granularity and loss of motility (6). Initial experiments verified that neither cytokines (IFN-y, TNF-a, IL-1, IL-2, IL-6) nor reagents (LPS, L-NMMA, L-NNA) were directly toxic to the larvae at the concentrations used.…”

Human Immune Responses toSchistosoma mansoniVaccine Candidate Antigens

“…The protective immune responses differ in these experimental models, being mainly humoral (IgE and IgG2a) in rats and mixed cellular and humoral in mice (13,14,34,38,39,41,42,51,52,59). Although human immune responses to S. mansoni have been studied extensively, the mechanism by which humans resist schistosome infection are still unclear.…”