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      Topical pimecrolimus inhibits high-dose UVB irradiation-induced epidermal Langerhans cell migration, via regulation of TNF-α and E-cadherin

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          Topical pimecrolimus has been shown to reverse epidermal CD1a + Langerhans cell reduction induced by high-dose ultraviolet (UV)B irradiation, but the mechanism is still unclear. This study aimed to investigate the possible mechanism of the effect of pimecrolimus on high-dose UVB-irradiated epidermal Langerhans cells.


          Forty human foreskin tissues were divided into four groups: control; pimecrolimus-only; UVB-only; and UVB + pimecrolimus. All tissues were cultured, and each tissue was cut into four pieces, corresponding to four time points (0 hours, 18 hours, 24 hours, and 48 hours). We collected the tissues and culture medium at each time point. The percentage of CD1a + cells in medium was detected by flow cytometry. The tissues were detected for messenger (m)RNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and E-cadherin, by reverse-transcription polymerase chain reaction (PCR) and Western blot.


          At 18 hours, 24 hours, and 48 hours, the CD1a + cells in the culture medium of the UVB-only group and the UVB + pimecrolimus group were significantly more than in the control group, while the CD1a + cells of the UVB + pimecrolimus group was less than of the UVB-only group. For both the UVB-only group and UVB + pimecrolimus group, TNF-α expression (by both reverse-transcription PCR and Western blot) of the tissues was clearly higher and E-cadherin expression was significantly lower compared with the control group, at 18 hours, 24 hours, and 48 hours. For the UVB + pimecrolimus group, TNF-α was clearly lower and E-cadherin was significantly higher compared with the UVB-only group.


          Topical pimecrolimus inhibited epidermal Langerhans cell migration induced by high-dose UVB irradiation, via regulation of TNF-α and E-cadherin.

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          Most cited references 21

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          CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.

          The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
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            Cc Chemokine Receptor (Ccr)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)-Inducing Dendritic Cells

            There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cells (DCs) and T cells. We tested the hypothesis that the CC chemokine receptor (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)-1α, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1α led to distinct defects in DC biology. Langerhans cell (skin DC) density in CCR2-null mice was normal, and their ability to migrate into the dermis was intact; however, their migration to the draining lymph nodes was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen, and this was primarily due to a reduction in the CD8α1 T helper cell type 1 (Th1)-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection–induced relocalization of splenic DCs from the marginal zone to the T cell areas. We propose that these DC defects, in conjunction with increased expression of B lymphocyte chemoattractant, a B cell–specific chemokine, may collectively contribute to the striking B cell outgrowth and Th2 cytokine–biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. This disease phenotype in mice with an L. major–resistant genetic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major–susceptible genetic background. Thus, CCR2 is an important determinant of not only DC migration and localization but also the development of protective cell-mediated immune responses to L. major.
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              Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells.

              Chemokines are known to regulate the steady-state and inflammatory migration of cutaneous dendritic cells (DCs). The beta-chemokine CCL17, a ligand of CCR4, is inducibly expressed in a subset of DCs and is strongly up-regulated in atopic diseases. Using an atopic dermatitis model, we show that CCL17-deficient mice develop acanthosis as WT mice, whereas dermal inflammation, T helper 2-type cytokine production, and the allergen-specific humoral immune response are significantly decreased. Notably, CCL17-deficient mice retained Langerhans cells (LCs) in the lesional skin after chronic allergen exposure, whereas most LCs emigrated from the epidermis of allergen-treated WT controls into draining lymph nodes (LNs). Moreover, CCL17-deficient LCs showed impaired emigration from the skin after exposure to a contact sensitizer. In contrast, the absence of CCR4 had no effect on cutaneous DC migration and development of atopic dermatitis symptoms. As an explanation for the major migratory defect of CCL17-deficient DCs in vivo, we demonstrate impaired mobility of CCL17-deficient DCs to CCL19/21 in 3D in vitro migration assays and a blockade of intracellular calcium release in response to CCR7 ligands. In addition, responsiveness of CCL17-deficient DCs to CXCL12 was impaired as well. We demonstrate that the inducible chemokine CCL17 sensitizes DCs for CCR7- and CXCR4-dependent migration to LN-associated homeostatic chemokines under inflammatory conditions and thus plays an important role in cutaneous DC migration.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                10 October 2014
                : 8
                : 1817-1825
                [1 ]Department of Dermatology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road, Nanjing, Jiangsu, People’s Republic of China
                [2 ]Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road, Nanjing, Jiangsu, People’s Republic of China
                Author notes
                Correspondence: Dan Luo, Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of China, Tel +86 0136 5518 7928, Fax +86 25 8371 6602, Email daniluo2005@ 123456sina.com

                *These authors contributed equally to this work

                © 2014 Yin et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                e-cadherin, pimecrolimus, tnf-α, langerhans cell, uvb


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