Interleukin 1 stimulates phosphatidylinositol kinase activity in human fibroblasts.
IL-1 mediates multiple cellular immune and inflammatory responses, but little is known of the intracellular biochemical mechanisms involved in IL-1 actions. We studied the effects of IL-1 on phosphatidylinositol (PtdIns) metabolism and confirmed reports indicating that IL-1 does not stimulate increased PtdIns turnover; however, we observed the accumulation of PtdIns-4-phosphate (PtdInsP) in response to IL-1. Using a fibroblast membrane preparation, we were able to detect stimulated PtdInsP accumulation within 10 s of IL-1 addition. Increased PtdInsP accumulation was due to stimulated PtdIns kinase activity, not the inhibition of PtdInsP hydrolysis by phospholipase(s). PtdIns kinase activity was magnesium dependent, increased as a function of IL-1 concentration, and specifically phosphorylated the D4 position of inositol. Stimulated PtdIns kinase activity could be detected at 10(-12) M IL-1 in fibroblast membranes, a concentration within the physiological range for IL-1 action; half-maximal activity was reached at approximately 10(-10) M IL-1. Heat denaturation of IL-1 or treatment of IL-1 with anti-IL-1 antibody abrogated the IL-1 effect. These findings demonstrate the direct, IL-1-mediated, stimulation of PtdIns kinase. IL-1-stimulated PtdIns kinase activity represents an important physiological regulatory effect by IL-1 as it could control the synthesis and/or maintenance of phosphorylated derivatives of PtdIns which comprise only a very small pool of substrates for the generation of the second messengers inositol 1,4,5-triphosphate and diacylglycerol.
Ballou
L R
LR
Research Service, Veterans Affairs Medical Center, Memphis, Tennessee.
Barker
S C
SC
Postlethwaite
A E
AE
Kang
A H
AH
D019870:1-Phosphatidylinositol 4-Kinase; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010770:Phosphotransferases / Q000032:analysis*
D007295:Inositol Phosphates; D007375:Interleukin-1; D010716:Phosphatidylinositols; D010770:Phosphotransferases; D019870:1-Phosphatidylinositol 4-Kinase; D008274:Magnesium