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American Journal of Pathology, Vol 138, 1097-1101, Copyright © 1991 by American Society for Investigative Pathology

REGULAR ARTICLES

Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation

TR Ulich, S Yin, K Guo, ES Yi, D Remick and J del Castillo
Department of Pathology, University of California, Irvine 91717.

The nature of the endogenous mediators that down-regulate and curtail the exodus of neutrophils into local acute inflammatory sites is unknown. In the present report, interleukin-6 (IL-6) and transforming growth factor beta (TGF beta), members of a family of macrophage- derived proteins known as cytokines, are shown to inhibit significantly the acute neutrophilic exodus caused by an intratracheal injection of endotoxin (LPS), a proinflammatory component of the cell walls of gram- negative bacteria. Transforming growth factor beta (10 micrograms) and IL-6 (10 micrograms) coinjected intratracheally with LPS (10 micrograms) each inhibited the number of neutrophils in 6-hour bronchoalveolar lavage (BAL) specimens by approximately 50%. The intratracheal coinjection of IL-6, TGF beta, and LPS inhibited the LPS- induced neutrophilic inflammatory exodus by nearly 75%. Interleukin-6 also is shown to be endogenously upregulated within the lung after intratracheal challenge with endotoxin, providing evidence that IL-6 may represent an endogenous negative feedback mechanism to inhibit endotoxin-initiated cytokine-mediated acute inflammation. Interleukin-6 and TGF beta both strongly inhibited the quantity of TNF-alpha recovered in the BAL fluid of LPS-challenged rats, suggesting that downregulation of LPS-induced TNF-alpha production within the lung represents one mechanism whereby IL-6 and TGF beta exert an antiinflammatory action. Interleukin-6 and TGF beta represent novel pharmacologic and, probably, endogenous inhibitors of acute inflammation.

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