Transforming growth factor beta 1 alters rat peritoneal macrophage mediator production and improves survival during endotoxic shock.
Transforming Growth Factor beta 1 (TGF-beta 1) is a potent anti-inflammatory cytokine involved in wound healing. Because of its anti-inflammatory actions, the effects of TGF-beta 1 were studied in vitro on rat macrophage inflammatory mediator production and in vivo on Salmonella enteritidis endotoxin (LPS) induced lethality. TGF-beta 1's effect on stimulated rat peritoneal macrophage (MO) production of prostacyclin and nitric oxide were assessed via measurement of their stable metabolites, 6-keto-PGF-1 alpha and nitrite, respectively. TGF-beta 1 (10 ng/ml) pretreatment (3 hours) resulted in significant reductions (p < 0.05) of LPS (50 micrograms/ml) stimulated, lipid A (1 and 10 micrograms/ml) stimulated, arachidonic acid (16 microM) stimulated, and Ca++ ionophore (10 microM) stimulated MO 6-keto-PGF 1 alpha production. These data suggest that TGF-beta 1 inhibits LPS stimulated MO 6-keto-PGF-1 alpha production by acting at, or distally to, phospholipase A2, possibly at the level of cyclooxygenase in the arachidonic acid cascade. In a similar study, TGF-beta 1 pretreatment led to a significant (p < 0.05) reduction of LPS stimulated MO nitrite production. In subsequent studies, the effects of TGF-beta 1 were studied in vivo on rats challenged with lethal doses of LPS. Rats pretreated with TGF-beta 1 (250 ng/rat i.v.) exhibited a significant increase (p < 0.01, n = 15 rats/group) in mean survival time compared to control rats. The increased survival time of TGF-beta 1 pretreated rats with LPS shock may be due, in part, to altered production of MO mediators.
Pender
B S
BS
Department of Physiology, Medical University of South Carolina, Charleston 29425, USA. ben_pender@smtpgw.musc.edu
Chen
H
H
Ashton
S
S
Wise
W C
WC
Zingarelli
B
B
Cusumano
V
V
Cook
J A
JA
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D011464:Epoprostenol / Q000096:biosynthesis; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009573:Nitrites; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol