Retinoic acid reduces p11 protein levels in bronchial epithelial cells by a posttranslational mechanism

p11 is a member of the S100 family of proteins, is the cellular ligand of a nnexin II, and interacts with the carboxyl region of 85-kDa cytosolic phosp holipase A(2) (cPLA(2)), inhibiting cPLA(2) activity and arachidonic acid ( AA) release. We studied the effect of retinoic acid (RA) on PLA(2) activity in human bronchial epithelial cells and whether p11 contributes to these e ffects. The addition of 10(-6) M RA resulted in reduced p11 protein levels at 4 days, with the greatest effect observed on days 6 and 7. This effect w as dose related (10(-6) to 10(-9) M). RA treatment (10(-6) M) had no effect on cPLA(2) protein levels. p11 mRNA levels were unchanged at 6 and 8 days of treatment (correlating with maximum p11 protein reduction). Treatment wi th RA reduced p11 levels in control cells and in cells transfected with a p 11 expression vector, suggesting a posttranslational mechanism. Lactacystin (10(-6) M), an inhibitor of the human 26S proteasome, blocked the decrease in p11 observed with RA treatment. Compared with control cells (n = 3), RA -treated cells (n = 3) had significantly increased AA release after treatme nt with the calcium ionophore A-23187 (P = 0.006). Therefore, RA reduces p1 1 protein expression and increases PLA(2) activity and AA release.