Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia.
Activin A is a member of the transforming growth factor-beta superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1beta, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-mug dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases.
Jones
Kristian L
KL
Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
Mansell
Ashley
A
Patella
Shane
S
Scott
Bernadette J
BJ
Hedger
Mark P
MP
de Kretser
David M
DM
Phillips
David J
DJ
D028341:Activins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D016207:Cytokines / Q000502:physiology; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology*; D038681:Follistatin / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D038681:Follistatin; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C422405:activin A; C440499:lipopolysaccharide, Escherichia coli O111 B4; D028341:Activins