Cloning of a Gene for a Novel Epithelium-specific Cytosolic Phospholipase A2, cPLA2δ, Induced in Psoriatic Skin

Abstract

Psoriasis is a common skin disease characterized by hyperplastic regenerative epidermal growth and infiltration of immunocytes. The etiology of psoriasis is unknown, although several genetic and cellular factors have been elucidated. To find new psoriasis-related genes, we have cloned cDNAs that are differentially expressed between normal and psoriatic skins. Among these clones, we have identified a new gene that codes for a new member of the type IV cytosolic phospholipase A 2 (cPLA 2 ) family. We refer to this gene as cPLA 2 ␦. It encodes a polypeptide of 818 amino acids that has significant homology with known cPLA 2 proteins in the C2 and catalytic domains. The cPLA 2 ␦ gene was mapped to the 15q13-14 chromosomal locus, near to the locus of the cPLA 2 ␤ gene, from which it is separated by a physical distance of about 220 kb. To identify the phospholipase A 2 activity of cPLA 2 ␦, we transfected COS-7 cells with His-tagged cPLA 2 ␦. The cell lysate from these cells had calcium-dependent phospholipase A 2 activity. Northern blot analysis revealed that a cPLA 2 ␦ transcript of about 4 kb is expressed in stratified squamous epithelia, such as those in skin and cervix, but not in other tissues. In situ hybridization and immunohistochemistry revealed that cPLA 2 ␦ is expressed strongly in the upper spinous layer of the psoriatic epidermis, expressed weakly and discontinuously in atopic dermatitis and mycosis fungoides, and not detected in the epidermis of normal skin; cPLA 2 ␣ is not detected in either normal or psoriatic skin. These results suggest that cPLA 2 ␦ exhibits a unique distribution pattern compared with that of known cPLA 2 subtypes, and it may play a critical role in inflammation in psoriatic lesions.

Identification of Novel Cytosolic Phospholipase A2s, Murine cPLA2δ, ϵ, and ζ, Which Form a Gene Cluster with cPLA2β

“…The sizes of cloned ORF for murine cPLA 2 ␦, ⑀, and were 2,748, 2,625, and 2,565-bp long corresponding to 825 (molecular mass 93 kDa), 875 (100 kDa), and 855 (96 kDa) amino acid residues, respectively. Recently, human cPLA 2 ␦ was discovered in the psoriatic skin cDNA library (35). We figured it to be the orthologue of one of the novel murine cPLA 2 s based on its chromosomal localization and homology of the primary structure.…”

“…3). Expression of human cPLA 2 ␦ was reported to be restricted to fetal skin, uterine cervix, and prostate under normal conditions (35), but not detected in placenta. Murine cPLA 2 ␦ was not observed in prostate (Fig.…”

“…We obtained the cDNA of these cPLA 2 s along with cPLA 2 ␤ from murine tissues by RT-PCR. Recently reported human cPLA 2 ␦ is located within this gene cluster (35). We assigned murine cPLA 2 ␦ among three newly cloned cPLA 2 s by homology alignments and comparison of the relative chromosomal location.…”

“…A possible function for cPLA 2 ␥ is remodeling of membrane phospholipids (33,34). Recently, human cPLA 2 ␦ was identified as one of psoriasisrelated genes (35). Whereas extensive studies have been carried out for secretory PLA 2 (36,37), only limited information is available for the cPLA 2 family.…”

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

“…These mice demonstrate reduced fertility and reduced brain injury after cerebral ischaemia [6][7][8]. Three human paralogs of the cPLA 2 -α enzyme have also been identified, termed cPLA 2 -β, cPLA 2 -γ and cPLA 2 -δ [9][10][11]. Crystallographic studies of cPLA 2 -α demonstrated the presence of two domains, an N-terminal calcium-phospholipid-binding (C2) domain and a catalytic domain [12].…”