Transcriptional regulation of inflammatory secreted phospholipases A(2)

Secreted phospholipases A(2) is a family of small molecular weight and calc ium-dependent enzymes of which the members list is presently growing. Among these enzymes, the synovial type IIA and the type V phospholipases A(2) ar e involved in inflammation. Although their actual mechanism is still a subj ect of debate, new therapeutic strategies can result from the knowledge of the regulations of their gene expression. The human genes of the type IIA a nd type V phospholipases A(2) are located on the chromosome 1 at close posi tions and transcribed in reverse orientations. These genes can therefore be regulated by common elements but only the regulation of the type IIA phosp holipase A(2) gene expression has been extensively studied. Pro-inflammator y cytokines upregulate while the growth factors downregulate the type IIA p hospholipase A(2) gene expression. Interleukin-6 and interleukin-1 beta exe rt their effects at least partially at the transcriptional level. The trans criptional regulation of the type IIA phospholipase A(2) gene is cell- and species-specific. The activity of the human promoter is controlled by the C AAT-enhancer binding protein (C/EBP) factors while that of the rat promoter is regulated by nuclear factor kappaB (NF-kappaB) and C/EBPs. Furthermore, the human promoter is constitutively repressed in hepatocytes by single st rand DNA binding proteins whose effects are relieved by C/EBP factors while the glucocorticoid receptor interacts with C/EBPs in chondrocytes to achie ve full basal and interleukin-1 beta -stimulated transcription activity. Ot her factors like CTF/NFI and Spl might be involved in the regulation of bot h the rat and human promoter. Peroxisome proliferator-activated receptors c ould contribute to the stimulation of the rat promoter by NF-kappaB in vasc ular smooth muscle cells. The study of the coactivators and coinhibitors as sociated to these transcription factors will give a better understanding of the diversity and complexity of the transcriptional regulations of the typ e IIA phospholipase A(2) gene. (C) 2000 Elsevier Science B.V. All rights re served.