Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation.
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.
Ulich
T R
TR
Department of Pathology, University of California, Irvine 91717.
Yin
S
S
Guo
K
K
Yi
E S
ES
Remick
D
D
del Castillo
J
J
D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D015152:Blotting, Northern; D016207:Cytokines / Q000008:administration & dosage* / Q000494:pharmacology; D004731:Endotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D007267:Injections; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014132:Trachea; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta