Secretory phospholipases A2 as multivalent mediators of inflammatory and allergic disorders

Phospholipases A(2) (PLA(2)s) are enzymes responsible for mobilization of fatty acids, including arachidonic acid (AA), from phospholipids. These enzymes are classified as high-molecular-weight cytosolic PLA(2)s (cPLA(2)s) and low-molecular-weight secretory PLA(2)s (sPLA(2)s). There is increasing evidence that large quantities of sPLA(2)s are released in the plasma of patients with systemic inflammatory and autoimmune diseases. In addition, high levels of sPLA(2)s can be detected at sites of allergic inflammation including the upper airways of patients with rhinitis and the lower airways of patients with asthma. These extracellular enzymes play an important role in inflammation by releasing AA, which can be subsequently converted to proinflammatory prostaglandins and leukotrienes. Generation of AA mediated by sPLA(2)s occurs through different mechanisms, including (1) the direct hydrolysis of outer cell membrane phospholipids, (2) internalization and transfer of sPLA(2)s to intracellular pools of phospholipids enriched in AA, and (3) activation of cPLA(2)s. In addition, sPLA(2)s induce degranulation and production of cytokines and chemokines from a variety of cells involved in inflammatory and immune responses. These effects are exerted by mechanisms that are independent of the enzymatic activity and are mediated by the interaction of sPLA(2)s with specific or promiscuous membrane receptors. Therefore, sPLA(2)s may have an important role in inflammatory and allergic reactions by activating multiple mechanisms within inflammatory and immune cells, leading to the production of eicosanoids, cytokines and chemokines.