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American Journal of Pathology, Vol 141, 61-68, Copyright © 1992 by American Society for Investigative Pathology

REGULAR ARTICLES

Endotoxin-induced cytokine gene expression in vivo. IV. Expression of interleukin-1 alpha/beta and interleukin-1 receptor antagonist mRNA during endotoxemia and during endotoxin-initiated local acute inflammation

TR Ulich, K Guo, S Yin, J del Castillo, ES Yi, RC Thompson and SP Eisenberg
Department of Pathology, University of California, San Diego School of Medicine 92103.

After the intravenous (IV) injection of endotoxin, (lipopolysaccharide [LPS]), in the rat, interleukin-1 alpha/beta (IL-1 alpha/beta) mRNA expression peaks at 1 hour in whole organ RNA preparations of the lung, liver, spleen, and bowel. Interleukin-1 receptor antagonist (IL-1ra) mRNA peaks at 2 to 4 hours, consistent with the hypothesis that IL-1ra acts as an endogenous negative feedback mechanism to downregulate the proinflammatory effects of IL-1. After the intratracheal (IT) injection of LPS, however, IL-1 and IL-1ra mRNA levels in whole lung peak at 6 hours, concurrent with the maximum influx of neutrophils (PMNs) into the bronchoalveolar space. To address the cellular source of IL-1 and IL-1ra mRNA in the lung during acute pneumonitis, mRNA levels were studied in bronchoalveolar lavage (BAL) macrophages incubated with LPS in vitro for 6 hours as compared with BAL cells (95% PMNs) obtained 6 hours after IT injection of LPS. A much greater expression of IL-1 and IL-1ra mRNA was observed in PMN-rich BAL cells obtained after IT injection of LPS, suggesting that PMNs contribute substantially to IL-1 and IL-1ra mRNA expression. Fractionation of alveolar macrophage- enriched and PMN-enriched subpopulations from the BAL cells obtained at 6 hours after IT injection of LPS confirmed that neutrophils are a source of IL-1 and IL-1ra mRNA. The difference in the kinetics of IL-1 and IL-1ra mRNA expression in whole lung RNA preparations after IV and IT injections of LPS is due to the contribution of PMNs that appear in the lung in large numbers after IT injection. Finally, human peripheral blood PMNs were found to express IL-1ra mRNA and protein after in vitro incubation with LPS. PMNs may contribute to the up- and downregulation of their own accumulation by expressing both IL-1 and IL-1ra.

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