TNF-alpha suppresses the PDGF beta-receptor kinase

PDGF and TNF-alpha are both known to play important roles in inflammation, albeit frequently by opposing actions. Typically, TNF-alpha can attenuate P DGF beta-receptor signaling. Pretreatment of mouse 3T3 L1 fibroblasts with TNF-alpha: greatly diminished their proliferative response to PDGF. However , TNF-alpha affected neither the binding of PDGF-BB to cell surface recepto rs nor the total amount of PDGF beta-receptor in the cells, but decreased t he PDGF-induced in vitro kinase activity of the receptor. The phosphatase i nhibitor ortho-vanadate did not prevent this effect. Ortho-phosphate labeli ng of cells prior to TNF-alpha treatment and PDGF-BB stimulation confirmed a decrease of in vivo phosphorylation of the PDGF beta-receptor. Two-dimens ional mapping after tryptic cleavage as well as phosphoamino acid analysis demonstrated a general decrease in phosphorylation of all known tyrosine re sidues in the PDGF beta-receptor. The exact mechanism for this suppression remains to be clarified. (C) 2000 Academic Press.