Eph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34 ؉ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. IntroductionDendritic cells (DCs) are antigen-presenting cells (APCs) that dwell in all lymphoid and nonlymphoid organs and have the unique capacity to activate naive T cells. 1,2 DCs originate from the bone marrow and migrate as precursors through the bloodstream to nonlymphoid tissues. Tissue DCs (eg, the epidermal Langerhans cells) are at an immature stage and are able to capture antigens with high efficiency. Antigen-bearing cells migrate from the periphery toward lymphatic vessels to reach the lymphoid tissues and localize in T-cell-rich areas as mature interdigitating DC (IDCs). [3][4][5] At this site, IDCs efficiently present the processed antigens to naive T cells and induce specific immune responses. 1 Thus, migration constitutes an integral part of DC function. The recruitment of DCs to the tissue damage site and the subsequent migration of DCs into secondary lymphoid organs rely on a dynamic and complex series of events involving cell surface receptors, primarily selectins, and integrins, which mediate the initial engagement of rolling cells. 6,7 Cell activation by signaling molecules, such as chemokines, leads to the activation of adhesion molecules, and the high-affinity binding of activated integrins to endothelial ligands, or extracellular matrix proteins, produces tight adhesion, shape change, and diapedesis to localize in extravascular foci. Although the role of chemokines in DC migration has been studied in depth, 8 the roles of other molecules in regulating their tissue trafficking remain to be investigated.Interactions of Eph receptor tyrosine kinases with their membrane-bound ligands, the ephrins, are implicated in important developmental processes, including tissue morphogenesis, control of angiogenesis, and axonal guidance. 9,10 According to their structural features and their preference for different ephrins, Eph receptors have been divided into 2 groups: EphA (A1-A8) receptors bind preferentially glycosylphosphatidylinositol (GPI)-anchored ligands, the ephrin-A (A1-A5), whereas EphB (B1-B6) receptors bind transmembrane ligands, the ephrin-B (B1-B3) 11,12 that are phosphorylated after Eph/ephrin interaction. 13 An individual Eph receptor, however, has a wide variation in affinity for different ephrins. 11 For example, ephrin-A3 binds to EphA3, EphA2, EphA7, EphA5, and EphA4 with decreasing affinities. 11,12 Ephrins play important roles during axon guidance by providing a repulsive guidance signal to Eph receptor cells. Navigating growth cones or migrating cells expressing Eph receptors turn away f...

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Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-β1 (TGF-β1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1β (IL-1β) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). TβRI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-β1 blockade (anti-TGF-β1 siRNA, TGF-β1 blocking antibodies, TβRI kinase, p38 or Smad3 inhibitors). TβRI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1β significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-β1 expression, binding to TβRI, TβRI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-β1 secretion by hPASMC and hPAEC. TGF-β1 may then act as an autocrine factor on these cells, increasing NGF secretion via TβRI activation. Since NGF and TGF-β1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.