THE INFLUENCE OF MAJOR TRAUMA ON THE REGULATORY LEVELS OF INTERLEUKIN-1 (IL-1) AND IL-2 IN HUMAN MONONUCLEAR LEUKOCYTES

The monokine Interleukin-1 (IL-1) and the lymphokine IL-2 are playing a crucial role within the course of an intact cell mediated immune res ponse (CMI). It was the objective of this study to further elucidate t he cytokine associate mechanisms of dysfunctional T-cell activation fo llowing major burn and mechanical trauma. Via comparative analysis of mRNA expression and protein release the major regulatory levels of IL- 1 and IL-2 release under stressful conditions were to be determined in mitogen respectively LPS stimulated PBMC (peripheral blood mononuclea r cells) cultures on consecutiive days (D) 1, 3, 5, 7 and 10 post inju ry. Further, we wanted to scrutinize if inadequate IL-2 production pos t-trauma is possible due to a defective transduction of extracellular signals to the T-cell nucleus. In order to answer this question IL-2 m RNA expression and IL-2 protein release were determined in PBMC cultur es using the phosphokinase C (PKC) activator phorbol ester (PMA) as a costimulus together with PHA. When analyzing the cumulative data for I L-1beta we saw until D 5 post-trauma a considerable impairment of the protein release in LPS stimulated PBMC cultures and recovery thereafte r. In only a few individual PBMC cultures we saw a concurrence between the IL-1beta mRNA signal intensity and the protein production. In the majority of the autoradiographies analyzed, the mRNA expression for I L-1beta was considerably more distinct compared to controls while the corresponding protein release values were on control level or below. T hese results implicate that the suppression of IL-1beta post-trauma is regulated mainly on a posttranscriptional level. Since Prostaglandin E2 (PGE2) has been found to have a vigorous impact on the IL-1beta syn thesis on the translational level, we assume that the high PGE2 levels post-trauma inhibit - via cAMP - sufficient IL-1beta synthesis on the posttranscriptional level. IL-2 protein synthesis as well as mRNA exp ression in mitogen (PHA) stimulated PBMC cultures following trauma, wa s persistently and significantly depressed compared to controls during the time of observation. The addition of PMA as a costimulus to PHA, could induce very distinct mRNA signals for IL-2 with a signal intensi ty which was comparable to that found in the cells of healthy controls . Also the quantity of IL-2 protein release in the vast majority of al l patients PBMC cultures following PHA/PMA induction was within the co ntrol range. Thus, the restoration of adequate IL-2 synthesis followin g injury evidently reflects the increase of mRNA for IL-2 and was acco mplished through the administration of the phorbol ester as a costimul us, a compound which mimicks the action of essential second messenger and directly activates PKC. From these data we conclude, that impaired IL-2 production post-trauma is not so much due to a constitutional de fect but is most likely attributable to alterations in the transmissio n of signals for the cell membrane to the nucleus.