On the basis of these findings, we propose that cholinergic urticaria should be classified into 2 distinct subtypes. The first (nonfollicular) subtype shows strong positive reactions to autologous sweat and negative reactions to autologous serum. The second (follicular) subtype shows weak reactions to autologous sweat and positive reactions to autologous serum.
Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) is a member of the signal regulatory protein family in which the extracellular region interacts with its ligand, CD47. Recent studies have demonstrated that SHPS-1 plays an important role in cell migration and cell adhesion. We demonstrate in this study, using immunohistochemical and flow cytometric analyses, that murine Langerhans cells (LCs) express SHPS-1. Treatment of mice ears with 2,4-dinitro-1-fluorobenzene significantly reduced the number of epidermal LCs, and that reduction could be reversed by pretreatment with mAb to SHPS-1 or the CD47-Fc fusion protein. Treatment with the SHPS-1 mAb in vivo reduced the number of FITC-bearing cells in the lesional lymph nodes after the application of FITC to the skin. The SHPS-1 mAb inhibited the in vivo TNF-α-induced migration of LCs. The emigration of dendritic cells expressing I-Ab+ from skin explants to the medium was also reduced by the SHPS-1 mAb. We further demonstrate that the chemotaxis of a murine dendritic cell line, XS52, by macrophage inflammatory protein-3β was significantly inhibited by treatment with the SHPS-1 mAb or CD47-Fc recombinant protein. Finally, we show that migration of LCs was attenuated in mutant mice that lack the intracellular domain of SHPS-1. These observations show that the ligation of SHPS-1 with the SHPS-1 mAb or with CD47-Fc abrogates the migration of LCs in vivo and in vitro, which suggests that the SHPS-1-CD47 interaction may negatively regulate LC migration.
Thioredoxin (TRX) is a small ubiquitous protein, which regulates cellular redox status and scavenges reactive oxygen species. The present study was conducted to investigate the effect of TRX on ultraviolet (UV)-B-mediated inflammatory and apoptotic responses. Ear swelling after UV-B irradiation was significantly reduced in TRX-transgenic mice compared to wild-type mice. Administration i.p. of recombinant human TRX also reduced acute skin inflammatory reaction, such as skin erythema and swelling. Histologically, numbers of inflammatory cells including neutrophils and lymphocytes were significantly reduced and the average size of the caliber of blood vessels were also reduced in recombinant human TRX-injected mice. The number of apoptotic keratinocytes, in terms of sunburn cells, activated-caspase-3-positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were all significantly reduced in recombinant human TRX-injected mice. Immunohistochemical intensity of 8-hydroxy-2'-deoxyguanosine was strikingly reduced in recombinant human TRX-injected mouse. Western blotting showed that administration of recombinant human TRX attenuated duration of phosphorylation of p38 mitogen-activated protein kinases and intensity of phosphorylation of c-Jun N-terminal kinase in the early phase, which play important roles in inflammatory and apoptotic signaling. Collectively, these findings indicated that recombinant human TRX attenuated inflammatory and apoptotic responses caused by UV-B. Possible mechanisms for this might be via redox regulation of stress signaling and reduction of reactive oxygen species.
Recently, we reported that Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) plays an important role in the migration of Langerhans cells (LC). Here, we show that SHPS-1 is involved in the maturation of LC. Immunofluorescence analysis on epidermal sheets for I-A or CD86 revealed that LC maturation induced by 2,4-dinitro-1-fluorobenzene (DNFB) or by TNF-a was inhibited by pretreatment with an anti-SHPS-1 monoclonal antibody (mAb) or with CD47-Fc fusion protein, a ligand for SHPS-1. Further, FACS analysis demonstrated that I-A + LC that had emigrated from skin explants expressed CD80 or CD86, whereas CD47-Fc protein reduced CD80 high+ or CD86 high+ cells. CD47-Fc protein also reduced the upregulation of surface CD80 or CD86 by LC remaining in the skin explants. In SHPS-1 mutant mice, we observed that the up-regulation of surface CD86 and CCR7 by LC induced by DNFB as well as that of surface CD80 and CD86 by LC in skin explants was attenuated. Finally, contact hypersensitivity (CHS) response was suppressed in SHPS-1 mutant mice and in wild-type mice treated with an anti-SHPS-1 mAb. These observations indicate that SHPS-1 plays an important role in the maturation of LC ex vivo and in vivo, and that SHPS-1-CD47 interaction may negatively regulate CHS. IntroductionDC are potent antigen-presenting cells that play a crucial role in the initiation of immune responses to pathogens. Langerhans cells (LC) are specialized immature DC in the skin that reside in the suprabasal layers of the epidermis. When LC encounter exogenous antigens, including haptens and microorganisms, they capture and process them to generate MHC/peptide complexes on their surface. LC migrate from the epidermis to draining lymphoid tissues in order to initiate naive T cells and to present the MHC/peptide complexes to Correspondence: Dr. Tatsuya Horikawa, Division of Dermatology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017Japan Fax:+81-78-382-6149 e-mail: thorikaw@med.kobe-u.ac.jp Received 12/1/06Revised 13/9/06 Accepted 19/10/06 [DOI 10.1002/eji.200635864] Key words: Contact hypersensitivity Á Langerhans cells Á Maturation Á Src homology 2 domaincontaining protein tyrosine phosphatase substrate 1Abbreviations: CCR7: CC chemokine receptor 7 Á CHS: contact hypersensitivity Á DNFB: 2,4-dinitro-1-fluorobenzene Á LC: Langerhans cell Á SHPS-1: Src homology 2 domaincontaining protein tyrosine phosphatase substrate 1 Á SIRP a1: signal-regulatory protein a1 and . In mice, SHPS-1 is expressed in myeloid cells, including monocytes, macrophages and DC [25]. SHPS-1 is a transmembrane glycoprotein whose extracellular domain comprises three immunoglobulin-like domains with multiple N-linked glycosylation sites, while the cytoplasmic domain of SHPS-1 contains four tyrosine residues that form two ITIM [26]. SHPS-1 was initially discovered as a tyrosine-phosphorylated transmembrane protein that binds SHP-1 or SHP-2. IAP/CD47, an integrin-associated...
CD47 is a membrane-associated glycoprotein that suppresses the function of immune cells. We previously reported that Langerhans cells (LCs) express Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1), a ligand for CD47, which plays an important role in the regulation of their motility. In this study, we show that LCs also express CD47, and that ligation of CD47 with SHPS-1-Fc fusion protein in vivo diminishes the development of the contact hypersensitivity response. We further demonstrate that CD47 engagement affects immune functions of LCs. CD47 engagement in vivo significantly inhibits the emigration of LCs from the epidermis into draining lymph nodes following treatment with haptens and tumor necrosis factor-alpha. The emigration of dendritic cells from skin explants into the medium and the chemotaxis of murine XS52 dendritic cells were significantly reduced by treatment with SHPS-1-Fc or an anti-CD47 mAb. Under explant culture system, SHPS-1-Fc treatment suppressed the expression of CD80 and CD86 of LCs. These effects on LCs and contact hypersensitivity response of CD47 ligation were reversed by treatment with pertussis toxin. These results suggest that the ligation of CD47 inhibits the migration of LCs and the expression of B7 costimulatory molecules, which results in inhibition of the contact hypersensitivity response.
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