Fatty acids modulate transforming growth factor-beta activity and plasma clearance.
The activity and plasma clearance of transforming growth factor (TGF)-beta are known to be regulated by activated alpha2-macroglobulin (alpha2M*). This has been implicated in pathophysiological processes, but no small molecule compounds have been reported to modulate TGF-beta activity by affecting the interaction of TGF-beta and alpha2M*. Here, we demonstrate that fatty acids are capable of inhibiting complex formation of TGF-beta isoforms and alpha2M* as demonstrated by nondenaturing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This is dependent on carbon chain length (C20, C18, C16, C14 > C12 > C10), degree of unsaturation (polyunsaturated > saturated), and TGF-beta isoforms (TGF-beta1 > TGF-beta2 > TGF-beta3). Arachidonic acid, which is one of the most potent inhibitors, is also capable of dissociating TGF-beta-alpha2M* complexes, but higher concentrations are required. Arachidonic acid appears to inhibit TGF-beta-alpha2M* complex formation by binding specifically to alpha2M* as demonstrated by gel filtration chromatography. Arachidonic acid reverses the inhibitory effect of alpha2M* on TGF-beta binding, TGF-beta-induced growth inhibition, and TGF-beta-induced transcriptional activation in mink lung epithelial cells and affects plasma clearance of TGF-beta-alpha2M* complexes in mice. These results show that fatty acids are effective modulators of TGF-beta activity and plasma clearance and may be useful in treating human diseases through their effects on the interaction of TGF-beta and alpha2M*.
Ling
Thai-Yen
TY
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Huang
Yen-Hua
YH
Lai
Ming-Chih
MC
Huang
Shuan Shian
SS
Huang
Jung San
JS
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005227:Fatty Acids / Q000494:pharmacology*; D046911:Macromolecular Substances; D051379:Mice; D008907:Mink; D008954:Models, Biological; D020033:Protein Isoforms / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors / Q000378:metabolism
D005227:Fatty Acids; D046911:Macromolecular Substances; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins