P-gp is also expressed on a variety of immune cells like monocytes, DCs, T and B cells[14]and is involved in the efflux of inflammatory molecules such as steroids, prostaglandins and cytokines[14][19], suggesting a function in immunomodulation. stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b / mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF- and IFN-. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines. == Conclusions == Our data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherapy. == Introduction == Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), characterized by the presence of demyelinated lesions throughout the brain[1][4]. Experimental autoimmune encephalomyelitis (EAE) is a widely accepted animal model for MS, sharing its clinical, immunological and pathological characteristics[5]. The mechanisms of CNS inflammation in MS and EAE involve generation of autoreactive, myelin specific T helper (Th) cells in the peripheral lymphoid organs, which subsequently enter the brain, initiate an immune response and eventually cause damage of myelin sheaths and axonal loss[6]. Antigen-presenting cells like dendritic cells (DCs) are important regulators of immune responses by showing their captured antigens to specific T cells[7]. In general, the maturation status of DCs is definitely a key determinant of how the immune response will evolve[8],[9]. Molecules or proteins that regulate DC maturation and therefore control immune reactions are under considerable investigation, since this may provide tools for immune modulation. One possible candidate for immunomodulation is definitely P-glycoprotein (P-gp; ABCB1), a well-known multi-drug resistance (MDR) efflux pump, which transports a variety of substrates and medicines through the membrane against a concentration gradient at the cost of ATP hydrolysis[10],[11]. P-gp was originally found out like a prototypic transporter involved in MDR of tumor cells[12], and was the 1st drug efflux transporter to be recognized on blood-brain barrier endothelial cells[13]. P-gp is also indicated on a variety of immune cells like monocytes, DCs, T and B cells[14]and is definitely involved in the efflux of inflammatory molecules such as steroids, prostaglandins and cytokines[14][19], suggesting a function in immunomodulation. A limited number of studies possess implied that P-gp can modulate immune reactions by regulating the emigration of Langerhans cells to lymphoid organs[20]and APC maturation in vitro via IL-12 secretion[21], butin vivorelevance is definitely lacking. Despite the reports suggesting immune-related K-604 dihydrochloride functions of P-gp, data on how P-gp exerts its action during immune responses remains unfamiliar. Therefore, the goal of our study was to investigate the potential immunomodulatory part of P-gpin vivo. We here demonstrate that DCs from P-gp knockout mice (Mdr1a/1b/,[22]) are seriously impaired in their maturation and T cell stimulatory capacity. As a result, Mdr1a/1b/ mice displayed reduced clinical indicators of EAE, which coincided with decreased inflammation in the brain and an overall reduced T cell response. Taken together, our findings spotlight a novel immunomodulatory part for P-gp, which may open new therapeutic avenues to interfere in the pathogenesis of (auto)immune-related or inflammatory diseases. == Results == == Mdr1a/1b / Mice Have Reduced Clinical Indicators of EAE == EAE was induced in Mdr1a/1b/ and wild-type K-604 dihydrochloride mice using recombinant myelin oligodendrocyte glycoprotein (rMOG). Notably, Mdr1a/1b / mice showed significantly reduced medical indicators of disease (*p<0.05) compared to wild-type animals during K-604 dihydrochloride the acute (day time 15) and progressive (day time 29) phase of disease (Figure 1a,Table 1). Moreover, the total Rabbit Polyclonal to OR8K3 EAE score per animal was significantly reduced Mdr1a/1b/ mice compared to wild-type mice (Number 1b). The observed differences in medical signs were associated with decreased demyelination in the brain of Mdr1a/1b/ EAE animals (Number S1). Decreased demyelination in Mdr1a/1b/ animals coincided with diminished brain swelling as determined by the reduced numbers of infiltrated macrophages in EAE lesions during the acute (Number 2a,b) and progressive (Number 2e,f) phase of disease (seeTable S3for a detailed overview). Notably, almost no CD3+T cell infiltrates were observed in Mdr1a/1b / EAE lesions during the acute (Number 2c,d) and progressive (Number 2g,h) phase.