Dendritic Cells Require Multidrug Resistance Protein 1 (ABCC1) Transporter Activity for Differentiation

Abstract

Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C4 was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor

“…Interestingly, it has been shown that monocytederived dendritic cells require for differentiation multidrug resistance protein 1 (ABCC1) transporter activity, which actively transports LTC 4 out of the cell. 14 Similarly, the activity of both ABCC1 and CysLTs was crucial for CCL19-induced migration of dendritic cells to lymph nodes in vivo in a murine model. 15 In asthmatic patients peripheral blood dendritic cells migrate into the bronchial mucosa during allergic inflammation, 16 and pretreatment with the antileukotriene drug pranlukast significantly attenuates allergen-induced airways responses and alters circulating dendritic cells.…”

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

“…37 Similarly, ABCC1 was implicated in the differentiation of a thymoma cell line into CD4 þ CD8 þ cells. 38 Although these studies failed to identify the involved substrates and ABCC1 was not targeted by more specific molecular means, in both these reports it is hypothesized that ABCC1 is important to keep cells in an undifferentiated state, reiterating the possibility that ABC transporters may play a role in the differentiation of mature bone marrow cell types.…”

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

“…However, since MRP-1 levels in synovial T cells are rather moderate, a major contribution to a reduced response to MTX or antimalarial drugs remains elusive. Apart from its putative pharmacologic role in MTX extrusion, MRP-1 has an important physiologic function; it exports mediators of inflammation such as leukotriene C 4 , which triggers antigen-presenting dendritic cell migration to lymph nodes via chemoattraction by CCL19 (45,46). Since high levels of CCL19 have been identified in RA synovial tissue (47,48), MRP-1 may be instrumental in the homing of inflammatory cells in RA synovial tissue.…”