Inhibition of Breast Cancer Resistance Protein (ABCG2) in Human Myeloid Dendritic Cells Induces Potent Tolerogenic Functions during LPS Stimulation

Abstract

Breast cancer resistance protein (ABCG2), a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR) in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs). ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c+ mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs) abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c+ mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4+ T cells and promoted expansion of CD25+FOXP3+ regulatory T (Treg) cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer.

Endothelial cell tolerance to lipopolysaccharide challenge is induced by monophosphoryl lipid A

“…While the impact of enhanced ERK activation on tolerance is not known, in endothelial cells, ERK activation has been shown to have anti-inflammatory properties [36]. Indeed, support for the role of ERK in tolerance was demonstrated in dendritic cells where enhanced ERK activation rendered cells tolerant to LPS [38]. While the specific contribution of ERK in tolerance remains unknown, it is clear that TLR4 activation can induce tolerance via a variety of mechanisms [33].…”

Multixenobiotic resistance in Mytilus edulis : Molecular and functional characterization of an ABCG2- type transporter in hemocytes and gills

“…Interestingly, ABCG2 seems also to play a role in immune modulation. Indeed, the transporter participate to the differentiation of skin Langerhans cells (Van de Ven et al, 2012) and myeloid dendritic cells (Jin and al., 2014). Consequently, we may think that Mytilus edulis ABCG2 has an immune defense function in hemocytes besides the detoxification task.…”

Alarmins and Antitumor Immunity

“…Unstimulated resting DCs are often in an immature/tolerant status induced by suppressive cells and their cytokines present in the tumor microenvironment. 129,130 These immature DCs not only have poor ability to stimulate T cells, but also promote tumor growth by producing proangiogenic factors and enhancing endothelial cell migration that results in vasculogenesis. 131 The development of large number of phenotypically and functionally matured DCs is important in the battle against tumors.…”