A mechanism of interleukin-12 unresponsiveness associated with thermal injury.
An unresponsive state for the production of interleukin-12 (IL-12) is commonly observed in animals and patients with severe thermal injuries. In the present study, the participation of corticosteroids, prostaglandin E(2) (PGE(2)), and type 2 cytokines, which appeared in association with thermal injury, on the burn-associated IL-12 unresponsiveness was studied. These substances 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 stimulation with lipopolysaccharide (LPS), while 1037 pg/ml IL-12 was detected in sera of unburned mice equally stimulated with LPS. Almost complete restoration of the impaired IL-12 production was witnessed in TI-mice after treatment 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 treated 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-associated type 2 T cells. In addition, in the presence of 1 microg/ml LPS, naive macrophages 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 results 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.
Utsunomiya
T
T
Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Kobayashi
M
M
Herndon
D N
DN
Pollard
R B
RB
Suzuki
F
F
D000305:Adrenal Cortex Hormones / Q000502:physiology; D000818:Animals; D002056:Burns / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000145:classification / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012016:Reference Values; D013601:T-Lymphocytes / Q000502:physiology / Q000637:transplantation
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D018664:Interleukin-12; D015232:Dinoprostone