Lactadherin Inhibits Secretory Phospholipase A2 Activity on Pre-Apoptotic Leukemia Cells

Abstract

Secretory phospholipase A2 (sPLA2) is a critical component of insect and snake venoms and is secreted by mammalian leukocytes during inflammation. Elevated secretory PLA2 concentrations are associated with autoimmune diseases and septic shock. Many sPLA2’s do not bind to plasma membranes of quiescent cells but bind and digest phospholipids on the membranes of stimulated or apoptotic cells. The capacity of these phospholipases to digest membranes of stimulated or apoptotic cells correlates to the exposure of phosphatidylserine. In the present study, the ability of the phosphatidyl-L-serine-binding protein, lactadherin to inhibit phospholipase enzyme activity has been assessed. Inhibition of human secretory phospholipase A2-V on phospholipid vesicles exceeded 90%, whereas inhibition of Naja mossambica sPLA2 plateaued at 50–60%. Lactadherin inhibited 45% of activity of Naja mossambica sPLA2 and >70% of human secretory phospholipase A2-V on the membranes of human NB4 leukemia cells treated with calcium ionophore A23187. The data indicate that lactadherin may decrease inflammation by inhibiting sPLA2.

Lactadherin orthologs inhibit migration of human, porcine and murine intestinal epithelial cells

“…(), it could be implied that the beneficial bioactive effects of lactadherin in inhibiting inflammatory bowels disease pathology could rely less on induction of enterocyte migration and more on phagocytosis of opportunistic pathogens and apoptotic cells as well as induction of immunosuppressing regulatory T cells (Fava & Danese, ; Hanayama et al., ; Zhou, Gao, Yang, & Yuan, ). A compounding effect from novel evidence of lactadherin as phospholipase inhibitor presents a likely explanation to the anti‐inflammatory and ameliorating effect of lactadherin in inflammatory bowels disease (Nyegaard, Novakovic, Rasmussen, & Gilbert, ). Phospholipase inhibition directly correlates with inhibited arachidonic acid release, a crucial eicosanoid precursor utilized in corticosteroid treatment (Cronstein, Kimmel, Levin, & Martiniuk, ).…”

Dietary Proteins and Angiogenesis

“…Finally, a very recent article shows that secretory phospholipase A 2 activity is increased on pre-apoptotic leukemia cells and that lactadherin inhibits this activity, thus opening another way for potential uses of lactadherin, or lactadherin-like molecules [ 43 ].…”

Serum level of lactadhedrin (MFGE8) in inflamatory bowel disease

“…It is expressed in the majority of tissues and organs. The glycoprotein fulfils an important function within the intestinal epithelium through its participation in removing apoptotic cells via bridging the connections between phosphatidylserine and αVβ5 integrins on the surface of macrophages, as well as through limiting the production of some proinflammatory factors, such as interleukin 1β (IL-1β), tumor necrosis factor (TNFα) [4] and through its ability to inhibit the secretory form of phospholipase A2 [5]. Deficiency of the protein leads to accumulation of apoptotic cells and by the same token to pathological sustenance of the inflammatory reaction and tissue damage.…”