cPLA sub(2[alpha] gene activation by IL-1[beta] is dependent on an upstream kinase pathway, enzymatic activation and downstream 15-lipoxygenase activity: A positive feedback loop)

• Published in: Cellular signalling Vol. 23; no. 12; pp. 1944 - 1951
• Main Authors: Walters, Jewell N, Bickford, Justin S, Beachy, Dawn E, Newsom, Kimberly J, Herlihy, John-David H, Peck, Molly V, Qiu, Xiaolei, Nick, Harry S
• Format: Journal Article
• Language: English
• Published: 01-12-2011
• Subjects: Arachidonic acid; Calcium; eicosanoids; Enzymatic activity; Feedback; Fibroblasts; Gene expression; Inflammation; Lipoxygenase; Lung; MAP kinase; Metabolites; MKK3 protein; MKK6 protein; Phospholipase A2; Phospholipids; Phosphorylation; Signal transduction; Transcription activation
• ISSN: 0898-6568
• DOI: 10.1016/j.cellsig.2011.07.002

Cytosolic phospholipase A sub(2[alpha] (cPLA) sub(2)[alpha]) is the most widely studied member of the Group IV PLA sub(2 family. The enzyme is Ca) super(2)+-dependent with specificity for phospholipid substrates containing arachidonic acid. As the pinnacle of the arachidonic acid pathway, cPLA sub(2[alpha] has a primary role in the biosynthesis of a diverse family of eicosanoid metabolites, with potent physiological, inflammatory and pathological consequences. cPLA) sub(2)[alpha] activity is regulated by pro-inflammatory stimuli through pathways involving increased intracellular Ca super(2+ levels, phosphorylation coupled to increased enzymatic activity and de novo gene transcription. This study addresses the signal transduction pathways for protein phosphorylation and gene induction following IL-1[beta] stimulation in human fetal lung fibroblasts. Our results utilizing both inhibitors and kinase-deficient cells demonstrate that cPLA) sub(2)[alpha] is phosphorylated within 10 min of IL-1[beta] treatment, an event requiring p38 MAPK as well as the upstream kinase, MKK3/MKK6. Inhibition of p38 MAPK also blocks the phosphorylation of a downstream, nuclear kinase, MSK-1. Our results further demonstrate that the activities of both cPLA sub(2[alpha] and a downstream lipoxygenase (15-LOX2) are required for IL-1[beta]-dependent induction of cPLA) sub(2)[alpha] mRNA expression. Overall, these data support an MKK3/MKK6 right arrow p38 MAPK right arrow MSK-1 right arrow cPLA sub(2[alpha] right arrow 15-LOX2-dependent, positive feedback loop where a protein's enzymatic activity is required to regulate its own gene induction by a pro-inflammatory stimulus.)