Gly80Ser Polymorphism of Phospholipase A2-IID Is Associated with Cytokine Inducibility in A549 Cells

Abstract

Background: The Gly80Ser polymorphism in phospholipase A2-IID (PLA2G2D, NCBI SNP reference: rs584367) is associated with a loss in body weight in patients with chronic obstructive pulmonary disease (COPD). The T allele missense mutation results in the 80th amino acid of the PLA2G2D protein changing from a glycine (Gly; C allele) to a serine (Ser; T allele). COPD patients carrying Ser lose a significant amount of weight compared with those carrying Gly. The mechanism for this weight loss following carriage of this Ser allele has not been clarified. Objectives: We aimed to evaluate whether this allelic change alters PLA2 enzymatic activity and/or pro-inflammatory cytokine inducibility. Methods: A549 cells (a human pulmonary epithelial cell line) were transfected with PLA2G2D-Gly or PLA2G2D-Ser. We evaluated PLA2 activity and cytokine expressions in these cells. Results: The enzymatic activity of sPLA2 in A549-PLA2G2D-Ser cells did not differ from the A549-PLA2G2D-Gly cells. A549-PLA2G2D-Ser cells spontaneously produced higher levels of interleukin (IL)-6 and IL-8 than A549-PLA2G2D-Gly cells. Upon tumor necrosis factor-α stimulation, IL-6 and IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were elevated compared with those of A549-PLA2G2D-Gly cells. Upon hydrogen peroxide stimulation, IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were higher than those of A549-PLA2G2D-Gly cells. Conclusions:PLA2G2D-Ser enhances the expression of IL-6 and IL-8 compared with PLA2G2D-Gly. This enhanced cytokine expression observed with the allelic change in PLA2G2D may be associated with the body weight loss seen in COPD patients.

Impairment of Pulmonary Function is an Independent Risk Factor for Atrial Fibrillation: The Takahata Study

“…Recently, the clinical phenotype of COPD was suggested to be associated with chronic inflammation, not only in the lung, but in the whole body, resulting in various co-morbidities such as unexplained cachexia, osteoporosis, and diabetes mellitus 4. As we previously demonstrated, differences in genetic backgrounds in COPD patients are involved in this exaggerated inflammatory response 5-7.…”

The Involvement of Phospholipases A2in Asthma and Chronic Obstructive Pulmonary Disease

“…Among sPLA 2 s, sPLA 2 IID is also considered as a molecule involved in the course of COPD. A change of Gly80Ser in the sPLA 2 IID protein may be associated with body weight loss in patients suffering from COPD [19]. sPLA 2 IID can be also involved in control of inflammation by inhibition of CD4+, CD8+ T cells proliferation and induction of regulatory T cell differentiation [20].…”

Group IID, IIE, IIF and III secreted phospholipase A2s

“…COPD patients carrying sPLA 2 -IID(Ser80) lose a significant amount of body weight in comparison with those carrying sPLA 2 -IID (Gly80). Although this mutation does not affect the in vitro enzymatic activity of sPLA 2 -IID, it enhances the expression of IL-6 and IL-8 in A549 cells (a human pulmonary epithelial cell line) [53]. A molecular model of human sPLA 2 -IID has revealed substantial differences between the native and mutant forms in terms of channel opening and the surface area for interfacial binding contact [54].…”