Thiotaurine modulates human neutrophil activation

Neutrophils are well recognized as one of the major players during acute infl ammation.They are typically the fi rst leukocytes to be recruited to an infl ammatory site and can eliminate pathogens by multiple means. Two different microbicidal mechanisms occur within the neutrophils: the oxidative and the non oxidative systems. The oxygen-dependent mechanism acts through generation of reactive oxygen species (ROS), and the oxygen-independent mechanism acts through production of antimicrobial peptides and proteolytic enzymes. During infl ammation, neutrophils are activated in response to several agonists generating superoxide anion and other ROS by NADPH oxidase-dependent mechanisms. This functional response, termed oxidative burst, contributes to host defense, but it can also result in collateral damage of host tissues. NADPH oxidase is a multicomponent enzyme system that catalyzes NADPH-dependent reduction of oxygen to superoxide anion. NADPH oxidase is activated by a variety of agents including N -formyl-methionyl-leucyl-phenylalanine (fMLP) and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA). These stimuli trigger biochemical cascades leading to the phosphorylation of several proteins of the NADPH oxidase system. In addition to the well-documented PKC pathway, one of these cascades involves activation of members of the mitogen-activated protein kinase (MAPK) family. Several studies have demonstrated that MAPK pathways such as extracellular signal- regulated kinases (ERK) 1/2 and p38 MAPK are activated in human neutrophils. Taurine is the most abundant free amino acid in most animal tissues and plays an important role in several essential biological processes (Huxtable 1992 ). A large number of reports have demonstrated the key role of taurine and its derivatives in the innate immune response (Schuller-Levis and Park 2004 ). It is widely recognized that taurine and related compounds such as hypotaurine and taurine chloramine exert a regulatory role in acute infl ammation. The protection by taurine and its derivatives on infl ammatory injury may be due to modulation of NADPH oxidase activity. It is noteworthy that taurine chloramines decrease PMA-stimulated superoxide production in human neutrophils by inhibiting phosphorylation of subunits of NADPH oxidase, eventually blocking the assembly of NADPH oxidase complex. Recently, it has been shown that thiotaurine (2-aminoethane thiosulfonate), a biomolecule structurally related to hypotaurine and taurine, prevents spontaneous apoptosis of human neutrophils (Capuozzo et al. 2013 ) and counteracts the damaging effect of oxidants in diabetic rat (Budhram et al. 2013 ). Interestingly, thiotaurine contains a sulfane sulfur that can be released as hydrogen sulfi de (H 2 S). It has been shown that H 2 S plays relevant roles, modulating several pathophysiological processes, including infl ammation. Taken together, these observations raise the possibility that thiotaurine, analogously to taurine and its derivatives, could modulate neutrophil activation. Thiotaurine is a thiosulfonates (RSO 2 SH) which has been occasionally detectedamong the products of biochemical reactions involving sulfur compounds. Thiotaurine is a metabolic product of cysteine in vivo and is produced by a spontaneous transsulfuration reaction involving thiocysteine (RSSH) and hypotaurine (RSO2H). Moreover, a sulfurtransferase which catalyzes the transfer of sulfur from mercaptopyruvate to hypotaurine with production of thiotaurine has been also reported. In the present study, thiotaurine has been assessed for an activity on functional response of human neutrophils. The results reveal that thiotaurine modulates fMLP- and PMA-mediated activation of human neutrophils, by inhibiting total ROS generation and superoxide anion production. Compared with fMLP-activated neutrophils, PMA-activated neutrophils were more susceptible to thiotaurine inhibition, suggesting that thiotaurine may interfere with the PKC-dependent pathway of neutrophil activation.