MOLECULAR MECHANISMS OF DECREASED INTERLEUKIN-2 PRODUCTION AFTER THERMAL-INJURY

Background. Among the fundamental immunologic abnormalities induced by serious traumatic or thermal injury are alterations in T cell activat ion, reduced lymphocyte interleukin-2 (IL-2) production, and associate d depression of T lymphocyte proliferation. This study attempts to loc alize the cellular mechanisms underlying abnormal IL-2 production in t hermal injury. Methods. Following National Institutes of Health guidel ines, 150 A/J mice were anesthetized, subjected to a 20% full-thicknes s scald burn injury or sham burn, and killed at intervals from 4 to 21 days later; splenocytes were harvested for in vitro studies. For meas urement of IL-2 production, cells were cultured with either concanaval in A or a combination of the phorbol ester PMA, which directly activat es protein kinase C, and the calcium ionophore A23187, which increases intracellular calcium. Cytokine mRNA expression was measured by North ern blot analysis and IL-2 production by bioassay. Results. Both IL-2 production and IL-2 mRNA expression were consistently suppressed in co ncanavalin A-stimulated cells from burned mice compared with sham burn s. This suppression of IL-2 and IL-2 mRNA also occurred when T cells w ere activated with PMA and A23187, bypassing the earlier stages of the signal transduction mechanism. IL- 1beta and tumor necrosis factor-al pha mRNA expression were consistently increased in burned animals, ind icating that decreased IL-2 mRNA expression was specific to IL-2 and n ot representative of a global decrease in cytokine mRNA expression. Co nclusions. These results suggest that the principal cellular abnormali ties that result in altered T cell activation and IL-2 production afte r thermal injury lie downstream of the initiating signal transduction events and before IL-2 gene transcription.