Transglutaminase 2 and phospholipase A2 interactions in the inflammatory response in human Thp-1 monocytes

Abstract

Several experimental approaches have demonstrated that transglutaminase 2 (TG2) increased activity is involved in monocyte activation and inflammatory response. Preliminary results also demonstrate a TG-mediated post-translational modification of phospholipase A2 (PLA2), which catalyzes the release of arachidonic acid from its lipid storage sites. The control of PLA2-mediated production of eicosanoids has been found to be of great benefit for inflammatory disease treatment. However, the identification of the mechanisms of PLA2 activation is a very complex issue, because of the presence of multiple PLA2 forms. The aim of this study was to characterize the interactions between TG2 and sPLA2 in LPS-stimulated THP-1 cells, which were treated with TPA to induce early differentiated macrophage-type model. We demonstrated that increases in TG2 enzyme activity and protein expression may be considered an early event in monocyte/macrophage activation by LPS. Under these conditions, TG2 protein was co-immunoprecipitated with PLA2 by monoclonal antibody directed against the secretory form of the enzyme (sPLA2-V). Concomitantly, the PLA2 enzyme activity increased in TPA-treated cells exposed to LPS; these high levels of enzyme activity were significant reduced by R283, a site-specific inhibitor of TG2. Moreover, confocal laser scanning microscopy analysis of double-immunostained cytochemical specimens confirmed a co-localization of BAPA-labeled proteins and sPLA2-V in LPS-treated cells. These findings give evidence of a complex TG2/sPLA2-V, suggesting the possibility that sPLA2-V is a substrate for TG2. These results demonstrated that TG2 increases produced a sustained activation of PLA2 activity, suggesting a functional interaction between these enzymes in the regulation of inflammatory response.

Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways

“…We show that these include Tgm2, Wnt5a, and sPLA2-X, which regulate macrophage activation and extracellular matrix crosslinking. 35,53,54 Because our 3-week HDM model involved both infiltration of eosinophils caused by an adaptive T H 2 response and innate upregulation of LT biosynthetic enzymes in bronchial epithelial cells, we cannot discriminate the major source of cysLTs in our experiments. In a shorter (3-day) HDM model BALF cysLT levels were increased despite the absence of infiltrating eosinophils, indicating that resident cells, which recognize components of HDM through innate receptors, can contribute to cysLT production during airway inflammation in vivo.…”

“…Indeed, our data on human macrophages support the view that AECs might communicate with myeloid cells through Wnt5a, Tgm2, and sPLA2 to perpetuate cysLT production and remodeling. 27,28,53 The most striking age differences were observed for Tgm2 and sPLA2-X expression, which were both increased when mice were sensitized with HDM as adults instead of as neonates. Although age-dependent regulation of Tgm2 and sPLA2-X in lung inflammation has not been reported previously, a recent study has shown that aging increased the expression of another phospholipase (sPLA-IID), which contributed to immune suppression and lung damage during viral infection.…”

Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response

“…Accumulating data points to sequela that involves free fatty acid (FFA)-mediated initiation of adipocyte hypertrophy, which is followed by initiation of innate immune response by the hypertrophic adipocytes [34]. Previous studies have linked two TGM family members, TGM2 and F13A1, to adipose tissue biology and inflammation [25,26,[28][29][30][37][38][39]. In this study, we have investigated the differential expression of the whole TGM family in adipose tissue of MZ twins that are discordant in weight (Heavy-Lean twin pairs).…”

Monocyte-derived tissue transglutaminase in multiple sclerosis patients: reflecting an anti-inflammatory status and function of the cells?

“…The presence of low levels of TG2 in human monocytes is known for many years. Moreover, inflammatory factors have been shown to enhance TG2 levels in these cells [ 35 – 38 ]. Thus far, few studies have been performed to determine a physiological or pathological expression of TG2 in monocytes/macrophages in vivo.…”