English version of Japanese guidance for the use of oral Janus kinase inhibitors (JAK1 and TYK2 inhibitors) in the treatments of psoriasis.

This is the English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors (JAK1 and tyrosine kinase 2 [TYK2] inhibitors) in the treatments of psoriasis. Several cytokines, such as interleukin (IL)-6, IL-7, IL-12, IL-21, IL-22, IL-23, interferon (IFN)-α, and IFN-γ, are involved in the pathogenesis of psoriasis (including psoriatic arthritis). As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of psoriasis. JAK has four types: JAK1, JAK2, JAK3, and TYK2. Regarding the use of oral JAK inhibitors for the treatment of psoriasis in Japan, indications of the JAK1 inhibitor upadacitinib were extended also to psoriatic arthritis in 2021, and the use of the TYK2 inhibitor deucravacitinib for plaque-type psoriasis, pustular psoriasis, and erythrodermic psoriasis became covered by health insurance in 2022. This guidance was developed for board-certified dermatologists who specialize in the treatment of psoriasis and to promote the proper use of oral JAK inhibitors. In the package inserts and guides for appropriate use, upadacitinib and deucravacitinib are classified as a "JAK inhibitor" and a "TYK2 inhibitor", respectively, and it is possible that there may be differences in safety between the two drugs. The safety of these drugs will be evaluated for the future by the postmarketing surveillance for molecularly targeted drugs for psoriasis of the Japanese Dermatological Association.

English version of Japanese guidance for use of biologics for psoriasis (the 2022 version).

This is the English version of Japanese guidance for use of biologics for psoriasis (the 2022 version). As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Moreover, after 2015, three IL-17 inhibitors, the IL-17A antibody preparations secukinumab and ixekizumab, and an anti-IL-17 receptor antibody preparation brodalumab were marketed. Furthermore, after 2018, the anti-IL23p19 antibody preparations guselkumab and risankizumab, the TNF inhibitor certolizumab pegol, the IL-23 inhibitor tildrakizumab, and the anti-IL-17A/F antibody bimekizumab were marketed. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors, and patient background factors, sharing such information with patients. The followings can be listed as points to be considered for the selection of biologics: drug effects (e.g., strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g., infections, administration-related reactions, and relationships with other comorbidities), convenience for patients (e.g., hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration), and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

Patient perceptions of psoriatic disease in Japan: Results from the Japanese subgroup of the Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) survey.

The population-based Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) survey was designed to better understand patient and dermatologist perceptions of the disease burden of psoriasis (PsO) and their treatment expectations. UPLIFT was a cross-sectional, quantitative, online survey conducted in Europe, North America, and Japan between 2 March and 3 June 2020. In Japan, 391 patients reporting a diagnosis of PsO and/or psoriatic arthritis (PsA) were surveyed (75% had PsO alone, 23% had PsO and PsA, and 2% had PsA alone). Self-reported body surface area (BSA) data were available for 309 Japanese patients, with the majority (80%) reporting PsO-involved BSA ≤3 palms. Current symptoms of PsO were rated as moderate or severe by 43% of Japanese patients with BSA ≤3 palms, and severe by 44% of patients with BSA 4-10 palms. PsO frequently occurred in ≥1 special areas, most commonly the scalp in 76% of Japanese patients with BSA ≤3 palms, and ≥90% of those with BSA ≥4 palms. Furthermore, musculoskeletal symptoms in 42% of patients with PsO alone were suggestive of PsA. Whereas Japanese patients with BSA ≤3 palms mainly reported receiving topical therapy alone (34%) or no treatment (32%), 64% patients with BSA 4-10 palms reported receiving systemic therapy. Overall, 21% of Japanese patients with self-perceived mild symptoms of PsO and 48% of patients with special area involvement experienced at least a moderate impact of disease on quality of life (Dermatology Life Quality Index score >5). Moreover, patients and dermatologists differed in their perceptions of determinants of PsO severity and treatment, and office visit discussions. In general, these findings from the Japanese subgroup of the UPLIFT survey demonstrated that a high proportion of patients perceived their symptoms to be moderate or severe irrespective of the level of skin involvement, suggesting a persistent unmet treatment need.

Japanese guidance for use of biologics for psoriasis (the 2019 version).

As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Since 2015, three IL-17 inhibitors of secukinumab and ixekizumab, anti-IL-17A antibodies, and brodalumab, an anti-IL-17 receptor antibody, and two anti-IL-23p19 antibodies of guselkumab and risankizumab, have also been launched. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors and patient background factors, sharing such information with patients. The following can be listed as points to be considered for the selection of biologics: drug effects (e.g. strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g. infections, administration-related reactions and relationships with other comorbidities), convenience for patients (e.g. hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration) and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure.

INTRODUCTION: Long-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis. METHODS: Integrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies. RESULTS: Total ixekizumab exposure was 17,003.4 p-y (N = 5898); 2749 patients had ≥ 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2-7.0/100 p-y); serious infections (range 1.3-1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to 0.2/100 p-y in years 4-5); other malignancies (range 0.4-0.6/100 p-y); inflammatory bowel disease including ulcerative colitis and Crohn's disease (IR 0.2/100 p-y); and major adverse cardiovascular events (MACE) (range 0.3-0.7/100 p-y). Candidiasis was reported in 327 patients (IR 1.9/100 p-y), with the majority identified as mucocutaneous. The rate of injection site reactions was 15.5/100 p-y during year 1 and 2.0-2.3/100 p-y by years 3-5. CONCLUSIONS: The decrease in rates of TEAEs and the stable rates of SAEs, other malignancies and MACE during up to 5 years of ixekizumab dosing are consistent with previous reports describing a favorable safety profile of ixekizumab following shorter durations of exposure. FUNDING: Eli Lilly and Company.

Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized, placebo-controlled phase 3 trial.

Tofacitinib is an oral Janus kinase inhibitor. These post-hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52-week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo-treated patients advanced to tofacitinib at week 16. Primary efficacy end-points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment (PGA) of "clear" or "almost clear" (PGA response) at week 16. Other end-points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI-75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.

Safety and efficacy of adalimumab treatment in Japanese patients with psoriasis: Results of SALSA study.

The safety and efficacy of adalimumab were evaluated over 24 weeks in Japanese patients with psoriasis in routine clinical practice. In this multicenter, observational, open-label, postmarketing study, primary efficacy measures included the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) in all patients with psoriasis. In patients with psoriatic arthritis (PsA), the 28-joint Disease Activity Score (DAS28) and the visual analog scale (VAS) pain were also evaluated. Safety was assessed based on the frequency of adverse drug reactions (ADR). Among patients with psoriasis evaluated for efficacy (n = 604), significant improvements from baseline were observed in mean PASI and DLQI scores at weeks 16 and 24 (all P < 0.0001). Furthermore, in psoriasis patients without PsA, the PASI 75/90 response rates were 55.9%/28.4% at week 16 (n = 306) and 65.6%/43.3% at week 24 (n = 270), respectively. In patients with PsA evaluable for effectiveness, significant improvements from baseline were observed in PASI, DAS28 erythrocyte sedimentation rate, DAS28 C-reactive protein and VAS pain at weeks 16 and 24 (all P < 0.0001). ADR and serious ADR were reported by 26.1% and 3.3%, respectively, of 731 safety evaluable patients with psoriasis; no unexpected safety findings were noted. The safety profile and effectiveness of adalimumab for the treatment of psoriasis in a routine clinical setting were as expected in Japanese patients.

Japanese guidance for use of biologics for psoriasis (the 2013 version).

The clinical use of adalimumab and infliximab, human anti-tumor necrosis factor (TNF)-α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti-interleukin-12/23p40 (IL-12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up-to-date, evidence-based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics.

Signaling through CD40 ligand decreases CD80 expression on murine Langerhans cells and enhances IL-12 p40 production.

We previously showed that murine Langerhans cells (LC) express CD40 ligand (CD40L). In this study, we further investigated the function of CD40L on LC using agonistic antibodies and CD40L knockout (KO) mice. Signaling through CD40L decreased CD80 expression on LC 48 h after stimulation and the decrease was more remarkable in the presence of interferon-gamma (IFN-gamma). Signaling through CD40 enhanced the production of IL-12 p40 from LC, and simultaneous signaling through CD40L slightly augmented this effect. Addition of IFN-gamma further enhanced IL-12 p40 production. LC from CD40L KO mice expressed similar levels of surface molecules such as CD40, CD80, CD86, and MHC class II, compared with those from wild-type mice. However, they produced less amount of IL-12 p40 during 48 h after purification. These results suggest that signaling through CD40L on LC is important in regulating IL-12 production, which is critical for Th1 type immune responses.

Differential effects of LPS and TGF-beta on the production of IL-6 and IL-12 by Langerhans cells, splenic dendritic cells, and macrophages.

We examined modulatory effects of lipopolysaccharide (LPS) on IL-6 and IL-12 production by mouse Langerhans cells (LC), spleen-derived CD11c+ dendritic cells (DC), and macrophages (Mphi). Low dose LPS (1 ng/ml) increased IL-6 and IL-12 p40 production by Mphi. LPS slightly augmented IL-6 production but showed no effect on IL-12 p40 production by DC. In contrast, only high dose LPS (1 microg/ml) induced IL-6 but not IL-12 p40 production by LC. CD14 expression was the highest on Mphi and then on DC, but not on LC, which may explain the difference in responsiveness to LPS. We also found that TGF-beta inhibited IL-6 and IL-12 p40 production by LPS-stimulated Mphi. However, TGF-beta did not inhibit IL-6 production and even enhanced IL-12 p40 production by anti-CD40/IFN-gamma-stimulated Mphi. Concerning LC, TGF-beta enhanced IL-6 and IL-12 p40 production when stimulated with anti-CD40/IFN-gamma alone or with anti-CD40/IFN-gamma and LPS. Taken together, these findings indicate diverse effects of LPS and TGF-beta on these antigen presenting cells, which probably represents their differential roles in the innate immunity.

Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A2, cPLA2delta, induced in psoriatic skin.

Psoriasis is a common skin disease characterized by hyperplastic regenerative epidermal growth and infiltration of immunocytes. The etiology of psoriasis is unknown, although several genetic and cellular factors have been elucidated. To find new psoriasis-related genes, we have cloned cDNAs that are differentially expressed between normal and psoriatic skins. Among these clones, we have identified a new gene that codes for a new member of the type IV cytosolic phospholipase A(2) (cPLA(2)) family. We refer to this gene as cPLA(2)delta. It encodes a polypeptide of 818 amino acids that has significant homology with known cPLA(2) proteins in the C2 and catalytic domains. The cPLA(2)delta gene was mapped to the 15q13-14 chromosomal locus, near to the locus of the cPLA(2)beta gene, from which it is separated by a physical distance of about 220 kb. To identify the phospholipase A(2) activity of cPLA(2)delta, we transfected COS-7 cells with His-tagged cPLA(2)delta. The cell lysate from these cells had calcium-dependent phospholipase A(2) activity. Northern blot analysis revealed that a cPLA(2)delta transcript of about 4 kb is expressed in stratified squamous epithelia, such as those in skin and cervix, but not in other tissues. In situ hybridization and immunohistochemistry revealed that cPLA(2)delta is expressed strongly in the upper spinous layer of the psoriatic epidermis, expressed weakly and discontinuously in atopic dermatitis and mycosis fungoides, and not detected in the epidermis of normal skin; cPLA(2)alpha is not detected in either normal or psoriatic skin. These results suggest that cPLA(2)delta exhibits a unique distribution pattern compared with that of known cPLA(2) subtypes, and it may play a critical role in inflammation in psoriatic lesions.

Lack of association between the promoter polymorphisms at positions -308 and -238 of the tumor necrosis factor alpha gene and psoriasis vulgaris in Japanese patients.

BACKGROUND: Psoriasis features an increased level and activity of tumor necrosis factor alpha (TNF-alpha). The TNF-alpha gene has single nucleotide polymorphisms (SNPs) at positions -308 (-308G>A) and -238 (-238G>A) in the promoter region, and the -238G>A SNP has been reported to be associated with psoriasis vulgaris (PV) and psoriatic arthritis in Caucasians. OBJECTIVE: To examine whether these SNPs are associated with susceptibility to PV in Japanese patients, we investigated the genotype and allele frequencies at each SNP in Japanese PV patients and in controls. METHODS: We examined 163 PV patients and 96 healthy individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant association between the genotypes or alleles of these SNPs and susceptibility to PV was observed. CONCLUSION: These SNPs themselves are not associated with susceptibility to PV in the Japanese.

Analysis of gene mutations in three cases of dermatofibrosarcoma protuberans (DFSP): ordinary DFSP, DFSP with fibrosarcomatous lesion (DFSP-FS) and lung metastasis of DFSP-FS.

BACKGROUND: Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor B-chain (PDGFB) gene has been pointed out in dermatofibrosarcoma protuberans (DFSP). Various exons of the COL1A1 gene have been shown to be involved in the fusion with exon 2 of the PDGFB gene. OBJECTIVE: We studied the breakpoints of the COL1A1 gene using the tumor specimens from three patients with DFSP. METHODS: Reverse transcriptase-polymerase chain reaction (PCR) was performed using cultured DFSP tumor cells or frozen tissue. Nucleotide sequence analysis was carried out using the PCR products to identify the breakpoints. RESULTS: Cases 1, 2 and 3 were diagnosed as ordinary DFSP, DFSP with fibrosarcomatous lesion (DFSP-FS) and lung metastasis of DFSP-FS, respectively. The COL1A1-PDGFB fusion transcripts were detected from the tumor specimens. Sequence analysis revealed that the ends of exons 42, 29 and 38 in the COL1A1 gene were fused with the start of exon 2 in the PDGFB gene in case 1, 2 and 3, respectively. CONCLUSION: This study identified a novel COL1A1 breakpoint, namely, exon 42 of the COL1A1 gene. Detection of the aberrant fusion transcript seems to be useful at differential diagnosis both in primary and metastatic lesions.

Thymus and activation-regulated chemokine (TARC/CCL17) produced by mouse epidermal Langerhans cells is upregulated by TNF-alpha and IL-4 and downregulated by IFN-gamma.

Thymus and activation-regulated chemokine (TARC/CCL17) is a Th2-type chemokine and its receptor CC chemokine receptor 4 (CCR4) is preferentially expressed on Th2 cells. Langerhans cells (LC) are immature dendritic cells (DC) in the epidermis of the skin and play vital roles in immune response. In this study, we investigated TARC expression by murine freshly isolated LC and 48 h cultured (mature) LC, and the regulation of TARC production in cultured LC by various cytokines. Murine LC was prepared using a panning method from BALB/c mice. RT-PCR was performed using fresh and cultured LC to evaluate TARC mRNA levels. ELISA was carried out using supernatant of cultured LC to calculate secreted TARC protein levels. TARC mRNA was strongly upregulated during maturation of murine LC. TARC production by murine LC was upregulated by TNF-alpha and IL-4 and downregulated by IFN-gamma, dose-dependently. Th1 and Th2 cytokines reciprocally regulate the production of Th2-type chemokine TARC by murine LC. Th2 cytokine microenvironments in skin may increase TARC production by mature LC, providing attraction of Th2 cells in skin. This may be an amplification circuit in Th2-dominant inflammatory skin disease like atopic dermatitis.

Both IL-4 and IL-13 inhibit the TNF-alpha and IFN-gamma enhanced MDC production in a human keratinocyte cell line, HaCaT cells.

BACKGROUND: Macrophage-derived chemokine (MDC) is a Th2 type chemokine and its receptor CC chemokine receptor 4 (CCR4) is preferentially expressed on Th2 cells. Recent reports demonstrated that MDC is expressed not only by macrophages, dendritic cells and lymphocytes, but also by cultured human keratinocytes (KCs). However, the regulation of MDC production in KCs by various cytokines has not been well documented. OBJECTIVE: In this study, we investigated how Th1/Th2 cytokines regulate MDC production in a human KC cell line, HaCaT cells. METHODS: HaCaT cells were cultured with or without various cytokines for 24 h and RT-PCR was performed using these cells to evaluate MDC mRNA levels. ELISA was carried out using supernatant of HaCaT cells to calculate secreted MDC protein levels. RESULTS: MDC mRNA was weakly expressed in HaCaT cells, and upon stimulation with TNF-alpha or IFN-gamma, MDC expression was strongly upregulated. The supernatant MDC levels when stimulated with TNF-alpha or IFN-gamma were significantly higher than those without stimulation, and were synergistically increased when stimulated with a combination of TNF-alpha and IFN-gamma. Both interleukin-4 (IL-4) and IL-13 inhibited TNF-alpha and IFN-gamma enhanced MDC production in HaCaT cells in a dose-dependent manner. CONCLUSION: Th2-type cytokines IL-4 and IL-13 downregulate the production of MDC, a Th2 type chemokine, by KCs. This may partially contribute to maintaining Th1/Th2 balance in inflammatory skin diseases like atopic dermatitis.

IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNF-alpha and IFN-gamma in HaCaT cell line.

It is known that both interleukin-4 (IL-4) and IL-13 are produced by Th2-type cells and share similar biological functions with each other. However, recently accumulated evidences have revealed that IL-4 may be involved in the Th1-type response. Both thymus and activation-regulated chemokine (TARC/CCL17), a ligand for CC chemokine receptor 4 that is mainly expressed on Th2-type cells, and interferon-induced protein of 10kDa (IP-10/CXCL10), a ligand for CXC chemokine receptor 3 that is mainly expressed on Th1-type cells, are produced by keratinocytes after the stimulation with the primary cytokines such as tumor necrotic factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma). In this study, we investigated the regulation of TARC or IP-10 production from HaCaT cells, an immortalized human keratinocyte cell line, after stimulation with TNF-alpha, IFN-gamma, IL-4 and/or IL-13. Without stimulation, HaCaT cells did not produce TARC. When both TNF-alpha and IFN-gamma were added, they increased synergistically (P<0.003). In addition, when HaCaT cells were stimulated with IL-4, but not IL-13, in combination with TNF-alpha and IFN-gamma, the supernatant TARC levels significantly decreased compared to those with both TNF-alpha and IFN-gamma (P<0.009). This inhibition was completely abolished with the addition of neutralizing anti-IL-4 antibody. The supernatant IP-10 levels also increased synergistically by stimulation with TNF-alpha and IFN-gamma for 24h (P<0.001). When IL-4, but not IL-13, was added to the medium and the cells were co-cultured with these cytokines, the IP-10 levels significantly increased compared to those with both TNF-alpha and IFN-gamma (P<0.04). Furthermore, the effects of IL-4 on TARC and IP-10 production in these cells were detected in a dose-dependent manner. These data strongly suggest that IL-4 may act not only as a mediator of Th1-type response but also as a down-regulator of Th2-type response in terms of the regulation of chemokine production by HaCaT cells.

Catecholamines inhibit the antigen-presenting capability of epidermal Langerhans cells.

The sympathetic nervous system modulates immune function at a number of levels. Within the epidermis, APCs (Langerhans cells (LC)) are frequently anatomically associated with peripheral nerves. Furthermore, some neuropeptides have been shown to regulate LC Ag-presenting function. We explored the expression of adrenergic receptors (AR) in murine LC and assessed their functional role on Ag presentation and modulation of cutaneous immune responses. Both purified LC and the LC-like cell lines XS52-4D and XS106 expressed mRNA for the ARs alpha(1A) and beta(2). XS106 cells and purified LC also expressed beta(1)-AR mRNA. Treatment of murine epidermal cell preparations with epinephrine (EPI) or norepinephrine inhibited Ag presentation in vitro. Furthermore, pretreatment of epidermal cells with EPI or norepinephrine in vitro suppressed the ability of these cells to present Ag for elicitation of delayed-type hypersensitivity in previously immunized mice. This effect was blocked by use of the beta(2)-adrenergic antagonist ICI 118,551 but not by the alpha-antagonist phentolamine. Local intradermal injection of EPI inhibited the induction of contact hypersensitivity to epicutaneously administered haptens. Surprisingly, injection of EPI at a distant site also suppressed induction of contact hypersensitivity. Thus, catecholamines may have both local and systemic effects. We conclude that specific ARs are expressed on LC and that signaling through these receptors can decrease epidermal immune reactions.