http://repub.eur.nl/res/aut/3285/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33171/ 2011-12-15T00:00:00Z The focus of this review is to discuss the pathogenesis and the pharmacotherapy of Hidradenitis suppurativa (HS). HS is a distressing chronic skin disorder characterized by abscesses, boils, fistulas and scarring, generally affecting the groins, anogenital area and axillae. It is a common disease with an estimated prevalence of 1%. The etiology is unknown. HS was thought to be a disease of the apocrine sweat glands, but histological findings indicate that HS is a disease arising from the hair follicles. Several pathogenic factors seem important including genetic predisposition, smoking, obesity and an aberrant immune response to commensal flora. The management of HS is tremendously challenging because effective therapies are lacking. Nevertheless, HS has been treated with topical and systemic antibiotics, retinoids and immunosuppressive drugs such as anti-TNF-α biologics with partial success. In this review we will also discuss a potential new therapy for HS with the anti-psoriases agent acitretin. http://repub.eur.nl/res/pub/34139/ 2011-11-01T00:00:00Z Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease. Since current treatments are unsatisfactory for many patients, there is a high need for effective drugs for this debilitating disease. Recent pathogenic insights suggest inflammasome activation and IL-1β production are important in HS. Colchicine is efficacious in the IL-1β- and inflammasome-mediated diseases gout, familial Mediterranean fever and Behçet's disease, and therefore a potentially effective drug in HS. Objective: To investigate the efficacy of colchicine in HS. Methods: In an open prospective pilot study, 8 HS patients were treated with the accepted gout maintenance regimen of 0.5 mg colchicine b.i.d. orally up to 4 months. Efficacy was assessed by a physician global assessment. Results: Colchicine treatment did not result in a clinically relevant improvement of disease severity. Three patients experienced nausea and diarrhea as known side effects. Conclusion: Colchicine in the used dose regimen does not ameliorate HS severity. Copyright http://repub.eur.nl/res/pub/26682/ 2011-07-01T00:00:00Z http://repub.eur.nl/res/pub/33387/ 2011-07-01T00:00:00Z Narrow-band ultraviolet-B (NB-UVB) phototherapy is an effective treatment for psoriasis. The molecular mechanisms underlying its efficacy are incompletely understood. To identify NB-UVB-induced molecular pathways that may account for its anti-inflammatory efficacy, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin from patients with psoriasis undergoing NB-UVB therapy. Downregulation of Th17 signaling pathway was observed during NB-UVB therapy in psoriatic epidermis. Strong inhibition of the Th17 pathway by UVB was confirmed in an ex vivo organ culture system by demonstrating reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation and Β-defensin-2 production. These results were further substantiated by demonstrating that NB-UVB inhibited the Th17-dependent psoriasis-like dermatitis in mice. Other pathways affected by NB-UVB therapy include the IFN signaling pathway, epidermal differentiation, and other well-known therapeutic targets in psoriasis, such as the glucocorticoid, vitamin D, peroxisome proliferator-activated receptor, and IL-4 signaling pathways. In conclusion, clinical improvement of psoriasis by NB-UVB is linked to suppression of Th17 and type I and type II IFN signaling pathways, which are critical in the pathogenesis of the disease. Our results show that clinically effective NB-UVB therapy is based on suppression of a broad range of important molecular pathways in psoriatic skin. http://repub.eur.nl/res/pub/26224/ 2011-06-01T00:00:00Z Background The pathogenesis of hidradenitis suppurativa (HS) is largely unknown and the disease is difficult to treat. Patients are in high need of an effective treatment. Although it is not known whether the levels of tumour necrosis factor (TNF)-α are aberrant in HS skin, anti-TNF-α biologics are used, with variable clinical efficacy. Objectives To determine the cytokine profile in lesional and perilesional HS skin. Methods We cultured 20 lesional and 10 normal-appearing perilesional HS skin samples, seven psoriasis and six healthy control skin samples in a transwell culture system. Two distinct cytokine bead arrays were used to measure the spectrum of inflammatory cytokines in the culture supernatant. Results from HS skin samples were compared with those of healthy and psoriasis skin. Results The proinflammatory cytokines interleukin (IL)-1β and TNF-α as well as the anti-inflammatory cytokine IL-10 were significantly elevated in HS skin. Elevated levels of these cytokines were also found in perilesional HS skin. Fold increases relative to control skin of IL-1β, TNF-α and IL-10 in HS were 31, 5 and 34, compared with psoriasis: 4, 1 and 2, respectively. Levels of all three cytokines showed a trend towards a positive correlation with disease severity. IL-2, IL-4, IL-5 and interferon-γ were hardly detectable in HS or healthy control skin. Conclusions This study shows for the first time that IL-1β, TNF-α and IL-10 levels are elevated in HS skin. These data provide a rationale for therapies with biologics targeting cytokines such as TNF-α and IL-1. © 2011 The Authors. BJD http://repub.eur.nl/res/pub/26372/ 2011-05-23T00:00:00Z Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions. Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction. http://repub.eur.nl/res/pub/25939/ 2011-04-11T00:00:00Z Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. http://repub.eur.nl/res/pub/26013/ 2011-04-01T00:00:00Z Background: The mode of action of narrowband ultraviolet B (NB-UVB) therapy in clearing psoriasis is incompletely understood, and in vivo studies at the molecular level in patients undergoing NB-UVB therapy are limited. We previously demonstrated increased expression and activity of double-stranded RNA (dsRNA) receptors in psoriasis lesions, and suggested that this enhanced innate signalling contributed to the maintenance of psoriatic inflammation. Objectives: We investigated whether NB-UVB affects dsRNA receptor expression and function in vivo as well as in vitro. Methods: Skin samples of patients with psoriasis undergoing NB-UVB treatment were analysed for epidermal messenger RNA (mRNA) expression of the various dsRNA receptors by microarray and quantitative reverse transcription-polymerase chain reaction. Primary human keratinocytes were irradiated with NB-UVB and stimulated with interferon (IFN)-α or IFN-γ, critical cytokines in psoriasis. The dsRNA analogue polyriboinosinic-polyribocytidylic acid was used to assess the functional responsiveness of the cells to dsRNA. Results: NB-UVB therapy of patients with psoriasis resulted in a significantly reduced mRNA expression of the activating dsRNA receptors MDA5 (IFIH1) and RIG-I (DDX58). On the other hand, expression of LGP2 (DHX58), toll-like receptor 3 (TLR3) and PKR (EIF2AK2) was not affected. In vitro, NB-UVB irradiation completely blocked the upregulation of four of the dsRNA receptors in primary human keratinocytes stimulated with IFN-α or IFN-γ, resulting in an attenuated inflammatory response to dsRNA. Conclusions: Our results show that NB-UVB irradiation inhibits the local innate inflammatory response to dsRNA, and suggest a novel mechanism of action of NB-UVB phototherapy in psoriasis. © 2011 The Author BJD http://repub.eur.nl/res/pub/26491/ 2011-04-01T00:00:00Z http://repub.eur.nl/res/pub/23334/ 2011-02-15T00:00:00Z IL-1F6, IL-1F8, and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control, uninvolved psoriasis, and psoriasis plaque skin using quantitative RT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriasis skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8, and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8, and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1α and TNF-α induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of antimicrobial peptides and matrix metalloproteinases by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of human β-defensin (HBD)-2, HBD-3, and CAMP and protein secretion of HBD-2 and HBD-3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies. http://repub.eur.nl/res/pub/20817/ 2010-09-01T00:00:00Z Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, often refractory to treatment. Patients with HS and dermatologists are in need of an effective, fast surgical intervention technique. Deroofing is a tissue-saving technique, whereby the "roof" of an abscess, cyst, or sinus tract is electrosurgically removed. The use of a probe is mandatory to explore the full extent of a lesion. Objective: We sought to evaluate the efficacy and patient satisfaction of the deroofing technique for recurrent Hurley I (mild) or II (moderate) graded HS lesions at fixed locations. Methods: An open study consisted of 88 deroofed lesions in 44 consecutive patients with HS, treated by a single clinician with a follow-up time of up to 5 years. Results: Fifteen of 88 (17%) treated lesions showed a recurrence after a median of 4.6 months. In all, 73 treated lesions (83%) did not show a recurrence after a median follow-up of 34 months. The median patient satisfaction with the procedure rated 8 on a scale from 0 to 10. Of the treated patients, 90% would recommend the deroofing technique to other patients with HS. One side effect occurred in the form of postoperative bleeding. Limitations: Some patients were lost to follow-up. Conclusions: The deroofing technique is an effective, simple, minimally invasive, tissue-saving surgical intervention for the treatment of mild to moderate HS lesions at fixed locations and it is suitable as an office procedure. http://repub.eur.nl/res/pub/27778/ 2010-03-01T00:00:00Z Background and Objectives: Pulsed dye laser (PDL) therapy is effective in clearing psoriasis plaques, but the mechanism of action is only partially understood. Local narrow-band ultraviolet B (NB-UVB), which has a better-defined mode of action, is an effective standard treatment for psoriasis. Our aim was to evaluate the cellular and molecular effects of PDL and to compare them with those of local NB-UVB in order to gain further insight into their mechanisms of action in psoriasis. Study Design/Patients and Methods: Nineteen patients with stable plaque-type psoriasis were treated either with PDL or NB-UVB. Lesional punch biopsies were obtained from all patients before treatment. Additional biopsies were obtained at 3 and 24 hours after PDL treatment in five of these patients. In 14 patients additional biopsies were taken after 7 and 13 weeks of treatment. Samples were histopathologically examined for the level of dermal T cell infiltrate, and the expression of epidermal β-defensin 2, immune cell-derived tumor necrosis factor (TNF)-α, endothelial E-selectin, vascular endothelial growth factor receptor (VEGFR) 2 and 3, and the expression of interleukin (IL)-23 before and after treatment. Results: The expression of VEGFR2, VEGFR3, and E-selectin was decreased in clinically high responders within 24 hours after PDL treatment. The expression of IL-23, TNF-α mRNA, and E-selectin protein were significantly reduced after two PDL treatments, whereas the expression of all epidermal markers and dermal T cell infiltrates had normalized after four treatments. The expression of epidermal activation markers and E-selectin were significantly reduced after 13 weeks of NB-UVB treatment. Conclusions: The expression of epidermal activation markers and the dermal T cell infiltrates were decreased after both treatments. The decreased expression of VEGFR2 and VEGFR3 followed by the down-regulation of TNF-α and IL-23p19 may be contributory factors in the efficacy of PDL in stable plaque-type psoriasis. http://repub.eur.nl/res/pub/27447/ 2010-01-01T00:00:00Z Background The co-occurrence of hidradenitis suppurativa (HS) and Crohn disease (CD) published in a few case reports resulted in the wide acceptance of an association between these two diseases. However, the combined prevalence of these diseases is currently unknown; furthermore, it is unknown whether this co-occurrence also applies for ulcerative colitis (UC). Objectives To estimate the prevalence of HS in patients with inflammatory bowel disease (IBD) living in the Southwest of the Netherlands. Methods During an IBD patient information meeting, randomly, 158 patients with IBD were interviewed about recurrent painful boils in the axillae and/or groin and were shown illustrative clinical pictures of the appearance of HS. Results Of the 158 patients interviewed, 102 (65%) had CD and 56 (35%) had UC. Twenty-five people (16%) responded that they had had or still experienced painful boils in the axillae and/or groin, of whom 17 were patients with CD (17%) and eight had UC (14%). Conclusions This pilot study shows for the first time that HS occurs in patients with CD or UC. More prospective studies are warranted to establish the association between HS and IBD and its underlying pathogenesis. http://repub.eur.nl/res/pub/24929/ 2009-08-01T00:00:00Z Background: A previous limited study showed promising results of combined oral treatment with rifampicin 600 mg and clindamycin 600 mg for 10 weeks. Objective: To expand and to validate the basis for this therapy, we reviewed the response to different treatment durations. Method: A retrospective study in 34 patients. Results: Twenty-eight of 34 patients (82%) experienced at least partial improvement, and 16 (47%) showed a total remission. The maximum effect of treatment appeared within 10 weeks. Following total remission, 8 of 13 (61.5%) patients treated as mentioned above experienced a relapse after a mean period of 5.0 months. Nonresponders were predominantly patients with severe disease. Conclusion: Combination treatment with oral rifampicin and clindamycin is a promising treatment option for hidradenitis suppurativa, despite the frequent occurrence of diarrhea as a side effect. The length and the dosage of treatment are not yet firmly established. Copyright http://repub.eur.nl/res/pub/25445/ 2009-05-01T00:00:00Z Topical application of imiquimod (IMQ), a TLR7/8 ligand and potent immune activator, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. Recently, a crucial role was proposed for the IL-23/IL-17 axis in psoriasis. We hypothesized that IMQ-induced dermatitis in mice can serve as a model for the analysis of pathogenic mechanisms in psoriasis-like dermatitis and assessed its IL-23/IL-17 axis dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions showed increased epidermal proliferation, abnormal differentiation, epidermal accumulation of neutrophils in microabcesses, neoangiogenesis, and infiltrates consisting of CD4+T cells, CD11c+dendritic cells, and plasmacytoid dendritic cells. IMQ induced epidermal expression of IL-23, IL-17A, and IL-17F, as well as an increase in splenic Th17 cells. IMQ-induced dermatitis was partially dependent on the presence of T cells, whereas disease development was almost completely blocked in mice deficient for IL-23 or the IL-17 receptor, demonstrating a pivotal role of the IL-23/IL-17 axis. In conclusion, the sole application of the innate TLR7/8 ligand IMQ rapidly induces a dermatitis closely resembling human psoriasis, critically dependent on the IL-23/IL-17 axis. This rapid and convenient model allows further elucidation of pathogenic mechanisms and evaluation of new therapies in psoriasis. Copyright http://repub.eur.nl/res/pub/25095/ 2009-01-01T00:00:00Z Background: Wet-wrap treatment (WWT) with diluted topical steroids is widely used in atopic dermatitis (AD). Mice with transgenic overexpression of human apolipoprotein C1 (APOC1) in the liver and the skin are not only characterized by hyperlipidaemia and raised IgE levels, but also by pruritic dermatitis and a disturbed skin barrier function, providing a novel in vivo mouse model for AD. Objectives: We investigated an adapted WWT method in the AD model in APOC1 mice in order to establish its efficacy. Methods: The effect of topical 0.1% and 0.03% tacrolimus ointment, tacrolimus base ointment, different dilutions of 0.05% fluticasone propionate (FP) cream and emollient on the development of dermatitis in APOC1 mice was investigated. WWT was performed with 0.03% tacrolimus ointment or 0.017% FP cream. Results: AD in APOC1 mice responded to topical treatment with tacrolimus or FP. In contrast to tacrolimus treatment, FP treatment was associated with loss of body weight. WWT reinforced several therapeutic aspects, notably improvements in transepidermal water loss and in epidermal thickness. WWT using tacrolimus 0.03% ointment was more effective than WWT using FP 0.017% cream. Conclusions: AD in APOC1 mice responds to treatment with (diluted) tacrolimus or FP; treatment with FP cream, but not tacrolimus ointment, was associated with weight loss. In this study, the adapted WWT using tacrolimus or FP in mice had a limited improving effect as compared with open application of tacrolimus or FP. http://repub.eur.nl/res/pub/29035/ 2008-05-01T00:00:00Z Mice with transgenic expression of human apolipoprotein C1 (APOC1) in liver and skin have strongly increased serum levels of cholesterol, triglycerides, and free fatty acids, indicative of a disturbed lipid metabolism. Importantly, these mice display a disturbed skin barrier function, evident from increased transepidermal water loss, and spontaneously develop symptoms of dermatitis including scaling, lichenification, excoriations, and pruritus. Histological analysis shows increased epidermal thickening and spongiosis in conjunction with elevated numbers of inflammatory cells (eosinophils, neutrophils, mast cells, macrophages, and CD4+ T cells) in the dermis. In addition, affected mice have increased serum levels of IgE and show abundant IgE+mast cells in the dermis. Partial inhibition of disease could be achieved by restoration of the skin barrier function with topical application of a lipophilic ointment. Furthermore, the development of atopic dermatitis in these mice was suppressed by corticosteroid treatment. These findings in APOC1(+/+) mice underscore the role of skin barrier integrity in the pathogenesis of atopic dermatitis. http://repub.eur.nl/res/pub/29114/ 2008-04-01T00:00:00Z Keratinocytes play a key role in innate immune responses of the skin to bacterial and viral pathogens. Viral double-stranded RNA and its synthetic analogue polyriboinosinic-polyribocytidylic acid (poly-IC) are recognized via multiple pathways involving the receptors Toll-like receptor 3 (TLR3), protein kinase R (PKR), and the recently described cytosolic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We show that preincubation of human keratinocytes with IFN-α enhances the proinflammatory responses to poly-IC. Kinetic studies suggest that this is mediated via upregulation of the receptors TLR3, PKR, RIG-I, and MDA5. Interestingly, expression of RIG-I, MDA5, and PKR was significantly increased in lesional skin from patients with psoriasis, a chronic inflammatory skin disease that is characterized by high IFN-α levels. These results suggest that psoriatic keratinocytes show increased sensitivity to viral RNA intermediates, thereby leading to excessive proinflammatory responses and maintenance of the inflammatory skin phenotype. Here, we provide early evidence that point toward a role for the recently described cytosolic innate RNA receptors in non-viral chronic inflammatory diseases. http://repub.eur.nl/res/pub/36552/ 2007-12-01T00:00:00Z http://repub.eur.nl/res/pub/36575/ 2007-10-01T00:00:00Z Psoriasis is a chronic inflammatory skin disease, characterized by a Th1 cytokine profile. We previously demonstrated that type I interferon (IFN-α/β) signaling is activated in psoriatic skin. Type I IFNs regulate the expression of many proinflammatory and anti-inflammatory cytokines, resulting in Th1 polarization. We assessed whether peripheral blood mononuclear cells (PBMC) from psoriatic patients show aberrant IFN-α responses. IFN-α stimulation caused a similar enhancement of IFN-γ and interleukin-10 (IL-10) secretion in psoriasis patients and controls, although the level of induction was variable. It was previously suggested that IFN-α-induced Th1 polarization is influenced by single nucleotide polymorphisms (SNPs) in the promoter of IFN regulatory factor-1 (IRF-1), a transcription factor involved in IFN signaling, providing a putative explanation for the observed variation. However, sequence analysis revealed no correlation between SNPs in the IRF-1 promoter and induction of IFN-γ or IL-10 expression. Furthermore, the frequency of the SNPs and psoriasis were not linked. Our data demonstrate that the described IRF-1 promoter SNPs do not play a role in the pathogenesis of psoriasis or in influencing IFN-α-induced Th1 polarization. We further demonstrate that psoriatic PBMCs do not respond aberrantly to IFN-α with respect to the production of the proinflammatory IFN-γ and the anti-inflammatory IL-10. http://repub.eur.nl/res/pub/35647/ 2007-01-01T00:00:00Z Psoriasis is a chronic inflammatory skin disease that is associated with an increased cardiovascular risk profile. The systemic inflammation present in psoriasis, various systemic treatments for psoriasis and an increased prevalence of unhealthy life style factors may all contribute to this unfavorable risk profile. The purpose of this article is to provide an overview of what is known about these risk factors in psoriasis, the way they influence the cardiovascular risk of psoriasis patients, and what can be done to reduce this risk. Genetic studies demonstrate that psoriasis and cardiovascular disease share common pathogenic features in which, for example inflammatory cytokines like TNF-α and IL-1 play an important role. The chronic inflammation in psoriasis has an unfavorable effect on the cardiovascular risk profile. Multiple cardiovascular risk factors seem to be influenced; the blood pressure, oxidative stress, dyslipidemia, endothelial cell dysfunction, homocysteine levels and blood platelet adhesion. Moreover, classic cardiovascular risk factors like smoking and obesity that have an increased prevalence among patients with psoriasis, indirectly also worsen the cardiovascular risk profile by stimulating the psoriasis activity. Systemic treatments in psoriasis reduce the cardiovascular risk by diminishing the inflammation, but it should be taken into account that most therapies also have adverse cardiovascular effects like dyslipidemia, hyperhomocysteinemia and hypertension. As a consequence preventive measures may be indicated at least during long-term treatments. Prospective research is warranted to accurately estimate the increased cardiovascular risk in psoriasis, to determine the underlying processes and to consider preventive measures according to the absolute risk of cardiovascular disease. The present overview provides data to advice health care providers to pay more attention to the cardiovascular risk profile in psoriasis patients. http://repub.eur.nl/res/pub/7767/ 2005-11-25T00:00:00Z http://repub.eur.nl/res/pub/9912/ 2002-01-01T00:00:00Z CD40 ligation by CD40 ligand(+) CD4(+) T cells has been claimed to be involved in inflammatory responses in human skin. However, these data are derived from in vitro cell culture systems and immunohistochemistry, and the mechanisms involved have not been fully elucidated. We previously observed that cells in intact normal human skin secrete high levels of IL-6 and IL-8 upon stimulation with IL-1 beta. In vitro studies have shown that CD40 ligation on human keratinocytes results in the production of IL-6 and IL-8 as well. We used a novel tissue culture system with intact normal human skin, and show that antibody ligation of CD40 results in the induction of several pro- and anti-inflammatory cytokines. IL-6, IL-8, tumor necrosis factor (TNF)-alpha, IL-12 and IL-1 beta were induced upon CD40 ligation and IFN-gamma stimulation, while IL-10 could be induced by CD40 ligation alone and was reduced again by the addition of IFN-gamma. Since CD40 ligation on monocytes and dendritic cells in vitro results in the secretion of IL-1, which is pre-stored in high concentrations in normal human keratinocytes, we subsequently investigated whether CD40 induced IL-6 and IL-8 production in skin is mediated via IL-1. Indeed IL-1 receptor antagonist inhibited the CD40 ligation-induced IL-6 and IL-8 production, while TNF-alpha and IL-10 production were not affected. These data show that CD40 ligation-induced secretion of IL-6 and IL-8, but not TNF-alpha and IL-10, is partially mediated via IL-1 and that IL-1 plays a prominent role in the inflammatory response initiated by CD40 ligation in intact human skin. http://repub.eur.nl/res/pub/39776/ 1992-11-04T00:00:00Z The above data show that prodigious alterations occur in the expression of cytokines and their receptors in psoriasis. Although a crucial role lor cytokines in the pathogenesis is almost definite, the results do not unequivocally demonstrate a primary cytokine defect in psoriasis. Furthermore, the data described are often contradictory. This may be caused by the use of different skin specimens, the detection of cytokines and receptors at different levels (eg. transcription, protein and bioactivity) combined with the use of different detection techniques. Despite the fact that data on cytokines in normal and psoriatic skin is far from complete, several alterations in psoriasis are evident: 1) dysregulation of IL-1; 2) increased levels of IL-6, IFN--y and especially IL-8 and TGF-a; 3) altered responsiveness of keratinocytes to IFN--y; and finally; 4) clearly increased expression of the EGFjTGF-a receptor. Taking these findings into account, psoriasis may be considered a multi-factorial immunological disease in genetically predisposed individuals with primary defect(s), probably residing in the cutaneous signalling system. A specifically altered cytokine profile in association with an altered response of the keratinocytes to these cytokines links inflammation with the hyperactive state in the epidermis in psoriasis. It is conceivable that this deviant cutaneous signalling system plays a central role in the pathogenesis of psoriasis. The aims of our studies were to further delineate the basic abnormalities in skin APC and the cutaneous cytokine network in psoriasis. The experimental work on APC, cytokines and cytokine receptors in the psoriatic skin are described in Chapters 3 to 7. In Chapter 8, the implications of our findings are discussed in the context of the literature data on the altered cytokine network in psoriasis.