Differential sensitivity of in vivo TNF and IL-6 production to modulation by anti-inflammatory drugs in mice.

The effect of dexamethasone and two non-steroidal anti-inflammatory agents ibuprofen and indomethacin on the production of serum interleukin 6(IL-6) and tumor necrosis factor (TNF) levels in mice treated with endotoxin (2.5 micrograms/mouse, i.p.) was investigated. Pretreatment of mice with dexamethasone (0.3-30.0 mg/kg, i.p., 30 min before endotoxin) completely blocked TNF production but did not affect that of IL-6. Conversely, pretreatment with indomethacin (5 mg/kg, i.p.) or ibuprofen (30 mg/kg, i.p.) potentiated the production of both IL-6 (+ 80% with INDO; + 100% with IBU) and TNF (+ 500% with INDO; + 50% with IBU). In the case of IL-6, the two anti-inflammatory drugs were able per se to induce significant levels of this cytokine even in the absence of LPS. These data indicate that IL-6 and TNF production are differently susceptible to glucocorticoids, and that prostaglandins can physiologically provide a negative feedback regulation of IL-6 and TNF synthesis.

The unique interaction with immunity of FCE 24517, an antitumor drug with a novel mode of action.

The present study was designed to characterize in mice the effects on the immune system of the antineoplastic agent FCE 24517, a benzoic acid mustard derivative of distamycin A with specificity for AT-rich base pair sequences of beta-DNA. At antitumorally therapeutic doses, single injections of FCE 24517 caused profound leukopenia and a decrease of spleen cell numbers. However, primary and secondary antibody production to the T-dependent antigen sheep red blood cells were markedly increased by FCE 24517 given before or together with antigen. Antibody production to the T-independent antigen type III pneumococcal polysaccharide was not appreciably affected by FCE 24517. The delayed type hypersensitivity response to sheep erythrocytes was only marginally decreased, whereas proliferation of spleen cells to mitogens was markedly depressed. The ability of natural killer cells and macrophages to mediate cytotoxicity was not affected by FCE 24517 treatment. The ability of carrier-primed cells from drug-treated mice to cooperate for anti-trinitrophenyl antibody production increased twofold over that of vehicle-injected controls, suggesting an increase in T-helper cell activity. Serum cytokine levels were studied in mice injected with bacterial lipopolysaccharide used as a model stimulus. Peak levels of TNF and IL-6 were not modified by FCE 24517, but at later times higher amounts of cytokines were found in drug-treated mice compared with the control, suggesting a longer exposure of immunocompetent cells to these factors. Two compounds (FCE 24561 and CC-1065), also capable of binding AT-rich sequences in the minor groove of beta-DNA and containing an alkylating moiety, had immunomodulatory activity similar to FCE 24517 in increasing primary anti-sheep erythrocytes response. It is concluded that FCE 24517 exhibits a unique interaction with the immune system, markedly different from that of alkylating agents and may be representative of a novel group of antiproliferative-immunomodulating agents.

Impairment of cytokine production in mice fed a vitamin D3-deficient diet.

C57Bl/6 female mice fed a Vitamin D (VIT-D)-deficient diet had serum levels of 25-hydroxyvitamin D decreasing with the time of diet exposure (3 and 8 weeks). Cytokine production (IL-6, TNF and IL-1) by peritoneal macrophages cultured in vitro with a standard stimulus, LPS, evaluated in the supernatants as biological activity, was significantly reduced in VIT-D-deficient animals. The defect in monokine production was partial and was evident at suboptimal LPS concentrations and incubation times. I-A antigen expression, induced in macrophages by in vitro exposure to IFN-gamma, was not modified in VIT-D-deficient mice, but IFN-gamma-inducible macrophage cytotoxicity to tumour target cells was significantly decreased in VIT-D-deficient animals. Moreover, basal and Poly I:C-induced NK activity was not modified by VIT-D deficiency. Thus, macrophage functions, such as cytokine production and tumour cytotoxicity induction, are down-modulated in vitro by VIT-D deprivation. To give more support to the relevance of VIT-D availability for cytokine production, TNF and IL-6 have been evaluated in the sera of control and VIT-D-deficient mice given LPS as a model stimulus. Serum peak levels of both cytokines were at least halved in VIT-D-deprived mice. Thus, VIT-D deficiency may represent a model of partial defect of monokine production.