Characterization of transglutaminase type II role in dendritic cell differentiation and function

Abstract

DCs play an essential role in the endotoxic shock, and their profound depletion occurs in septic patients and septic mice. TG2(-/-) mice are more resistant to the endotoxic shock induced by LPS. Here, we studied the cellular and molecular basis of this effect, analyzing the role of the enzyme in DC maturation and function. We show that TG2 is up-regulated drastically during the final, functional maturation of DCs consequent to LPS treatment. In keeping with this finding, the inhibition of the enzyme cross-linking activity determines the impairment of DC function highlighted by wide phenotypic changes associated with a reduced production of cytokines (IL-10, IL-12) after LPS treatment and a lower ability to induce IFN-gamma production by naïve T cells. The in vivo analysis of DCs obtained from TG2(-/-) mice confirmed that the enzyme ablation leads to an impairment of DC maturation and their reduced responsiveness to LPS treatment. In fact, a marked decrease in DC death, TLR4 down-regulation, and impaired up-regulation of MHCII and CD86 were observed in TG2(-/-) mice. Taken together, these data suggest that TG2 plays an important role in regulating the response of DCs to LPS and could be a candidate target for treating endotoxin-induced sepsis.

Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells

“…This hypothesis is corroborated by our previous work, in which we demonstrated that AE is able to induce the production of anticancer cytokines, such as IL-12, also in U937 leukemia cells (Tabolacci et al, 2011). Interestingly, it has been demonstrated that the serum levels of IL-12 and IFN-γ in TG2 À / À mice are significantly decreased (Falasca et al, 2005), as well as in dendritic cells after the inhibition of TG2 cross-linking activity (Matic et al, 2010). Another cytokine with anticancer activity, GM-CSF, was stimulated by AE.…”

Cellular Functions of Tissue Transglutaminase

“…TG2 was required for dendritic cell maturation from monocytes stimulated by bacterial LPS. The TG2-specific inhibitor KCC009 attenuated the development of dendritic cells and their production of cytokines, and genetic ablation of TG2 resulted in conferred resistance to LPS-induced septic shock (Matic et al, 2010). Of note, TG2 was dispensable for dendritic cells differentiation induced by GM-CSF and IL-4, suggesting the involvement of specific LPS receptors in the regulation of the TG2 functions.…”

Transglutaminase 2 modulates antigen-specific antibody response by suppressing Blimp-1 and AID expression of B cells in mice

“…Human monocytederived DCs have been shown to express TG2 on their surface, which expression increased when the cells were activated with bacterial lipopolysaccharide [11]. The lack of this enzyme rendered activated DCs less functional in cytokine secretion and the priming capacity of T cells [12]. Also, TG2 was up-regulated as much as 15-fold in human peripheral blood lymphocytes within 30 min of in vitro activation with concanavalin A [13], and T cells from HIVinfected patients showed elevated expressions of TG2 as a result of activation of these cells [14].…”