A mechanism of interleukin-12 unresponsiveness associated with thermal injury

An unresponsive state for the production of interleukin-12 (IL-12) is commo nly observed in animals and patients with severe thermal injuries. In the p resent study, the participation of corticosteroids, prostaglandin E-2 (PGE( 2)), and type 2 cytokines, which appeared in association with thermal injur y, on the burn-associated IL-12 unresponsiveness was studied. These substan ces have been described as inhibitors of IL-12 production. Less than 20 pg/ ml serum IL-12 was produced in thermally injured mice (TI-mice) after stimu lation with lipopolysaccharide (LPS), while 1037 pg/ml IL-12 was detected i n sera of unburned mice equally stimulated with LPS. Almost complete restor ation of the impaired IL-12 production was witnessed in TI-mice after treat ment with soluble IL-4 receptor (50 ng/mouse, 2 h and 2 days after thermal injury). However, IL-12 was not induced by LPS stimulation in TI-mice treat ed with an inhibitor of PGE(2) (indomethacin, 0.1-5 mg/kg) or an inhibitor of corticosteroid production (ketoconazole, 10 mg/kg). LPS-stimulated IL-12 production was also impaired in normal mice inoculated with burn-associate d type 2 T cells. In addition, in the presence of 1 mug/ml LPS, naive macro phages cocultured with burn-associated type 2 T cells did not produce IL-12 in their culture fluids, while IL-12 was produced by LPS-stimulated naive macrophages that were cocultured with naive splenic CD8(+) T cells. These r esults suggest that the IL-12-unresponsive state demonstrated in TI-mice is associated mainly with type 2 cytokines released from burn-associated type 2 T cells. (C) 2001 Academic Press.