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

The nature of the endogenous mediators that downregulate 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 (TGFβ), 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 μg) and IL-6 (10 μg) coinjected intratracheally with LPS (10 μg) each inhibited the number of neutrophils in 6-hour bronchoalveolar lavage (BAL) specimens by approximately 50%. The intratracheal coinjection of IL-6, TGFβ, 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 TGFβ both strongly inhibited the quantity of TNF-α recovered in the BAL fluid of LPS-challenged rats, suggesting that downregulation of LPS-induced TNF-α production within the lung represents one mechanism whereby IL-6 and TGFβ exert an antiinflammatory action. Interleukin-6 and TGFβ represent novel pharmacologic and, probably, endogenous inhibitors of acute inflammation.