Secretory Phospholipases A2 as Multivalent Mediators of Inflammatory and Allergic Disorders

Phospholipases A2 (PLA2s) are enzymes responsible for mobilization of fatty acids, including arachidonic acid (AA), from phospholipids. These enzymes are classified as high-molecular-weight cytosolic PLA2s (cPLA2s) and low-molecular-weight secretory PLA2s (sPLA2s). There is increasing evidence that large quantities of sPLA2s are released in the plasma of patients with systemic inflammatory and autoimmune diseases. In addition, high levels of sPLA2s 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 sPLA2s occurs through different mechanisms, including (1) the direct hydrolysis of outer cell membrane phospholipids, (2) internalization and transfer of sPLA2s to intracellular pools of phospholipids enriched in AA, and (3) activation of cPLA2s. In addition, sPLA2s 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 sPLA2s with specific or promiscuous membrane receptors. Therefore, sPLA2s 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.