Inflammatory Process In Psoriasis Research Articles

Serum calprotectin as a predictive biomarker in the treatment of psoriasis vulgaris with methotrexate

Background Psoriasis is a chronic inflammatory disease that poses a challenge in its pathogenesis and treatment. Calprotectin is upregulated in psoriatic epidermis and is supposed to have a role in the inflammatory process of psoriasis. Calprotectin was suggested as a biomarker to detect responders to methotrexate in juvenile idiopathic arthritis. Objective To evaluate the relation of calprotectin serum level and psoriasis severity and to assess if it can predict response to methotrexate and disease relapse after stoppage of the treatment. Patients and methods Thirty patients with psoriasis vulgaris and 30 controls were included. Serum calprotectin was measured in controls and in patients before and after methotrexate therapy for 3 months. The patients were followed up for 6 months to detect disease stability or relapse and its relation to calprotectin level at the end of therapy. Results Higher calprotectin level in psoriatic patients was detected before methotrexate treatment than after treatment. Significant positive correlation was found between serum calprotectin and psoriasis area and severity index score. Calprotectin was higher in patients before starting methotrexate in those defined as responders than nonresponders (P=0.015) and can predict response to treatment with a cutoff value of 60 ng/ml (sensitivity 82.35% and specificity 69.23%). The level of calprotectin was higher in patients during their clinical remission who relapsed after stoppage of methotrexate than the nonrelapsed cases (P=0.021) and can predict the relapse with a cutoff value of 56.5 ng/ml (sensitivity 66.67% and specificity 100%). Conclusion Calprotectin can be a marker of psoriasis severity. Higher level of baseline serum calprotectin can predict psoriatic patients who will improve on methotrexate therapy. In addition, higher calprotectin levels were associated with relapse risk after stoppage of methotrexate.

THE ROLE OF CYTOKINES OF INTERLEUKIN 36 FAMILY IN IMMUNOPATHOGENESIS OF PSORIASIS

Over last decade, the importance of immune mechanisms for development of psoriasis has expanded considerably. This review describes biological properties of the cytokines from the interleukin-36 (IL-36) family, and their role in pathogenesis of plaque psoriasis, generalized pustular psoriasis and psoriatic arthritis. Keratinocytes and dendritic cells (DC) are the main sources of IL-36 in the skin. Production of this cytokine is greatly enhanced by inflammation. The studies have shown that, in affected skin of psoriatic patients, an increased expression of IL-36α and IL-36γ is observed. IL-36γ can be considered a specific marker of psoriasis, which is not found in other inflammatory skin diseases (neurodermatitis, lichen planus, eczema). The levels of this cytokine correlate with severity of psoriasis and decreases after anti-TNFα therapy. High level of IL-36 cytokines in the areas of psoriatic eruptions correlates with increased concentrations of pro-inflammatory TNFα, IL-17, IL-22 and IFNγ in the skin. We present literature data on the role of IL-36RN mutation which encodes the IL-36ra receptor antagonist, playing a role in the development of generalized pustular psoriasis (GPP). Excessive activity of IL-36 agonists leading to accumulation of neutrophilic granulocytes in epidermis may be a key event in the GPP pathogenesis. The article deals with modern ideas about the role of neutrophilic granulocytes in development of chronic inflammatory processes underlying pathogenesis of psoriasis. Proteases of neutrophils (cathepsin G, elastase and proteinase-3) are potent IL-36 activating enzymes that increase activity of IL-36 cytokines up to 500 times. In this review, a new mechanism (netosis) is suggested for the role of neutrophils in immune response. During the netosis, a large number of cytokines, antimicrobial peptides, intracellular components, serine proteases are released into the extracellular space. Thus, they may be involved into initiation and maintenance of a chronic inflammatory process in psoriasis. The present information concerning a role of new IL-36 family cytokines as one of the main psoriasis mediators has opened new therapeutic goals for the treatment of this disease and development of new methods of targeted therapy. Specific blocking of IL-36R signaling, or inhibition of neutrophil proteases of cathepsin G, neutrophil elastase that activate members of the IL-36 family, is likely to be a successful strategy in the therapy of psoriasis.

The Role of IL-18, TNF-α and hs-CRP among Iraqi psoriatic Patients and their Correlation with Disease Severity

Psoriasis is a chronic inflammatory disease characterized by number of immune regulatory abnormalities. Cytokines are small, biologically highly active proteins that regulate the growth, function, and differentiation of cells and help directing the immune response and inflammation, contribute to the induction or persistence of the inflammatory processes in psoriasis. Intensive research is ongoing to understand the mechanisms involved in the development of psoriasis and offer new treatment options for patients suffering from this disease.This study was conducted to evaluate serum IL-18, TNF-α and hs-CRP levels among Iraqi psoriatic patients and to assess their relation to disease severity depending on Psoriasis Area and Severity Index (PASI). A 65 patients with psoriasis (42 females and 23 males), with mean age (35±13) years old, and 25 apparently healthy volunteers (15 females and 10 males) with no symptoms or history of psoriasis or other allergic or skin disorders (control group) were conducted in this study. Patients were divided into two groups according to the severity of their psoriasis, 20 cases diagnosed as moderate psoriasis (PASI ˂ 15) and 45 cases diagnosed as severe (PASI ≥ 15).The results demonstrated significant elevation of IL-18, TNF-α and hs-CRP levels in both groups of psoriatic patients compared with control group, and a significant positive linear correlation was found between IL-18, hs-CRP and severity of the disease.These results identify IL-18 and hs-CRP as mediators in the pathogenesis of psoriasis and can be considered as useful markers to assess psoriasis and may be considered as useful follow-up markers for monitoring patients with psoriasis.

Immunological Evaluation of Psoriatic Patients In Erbil City/Iraq

Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The immunopathogenesis of this disease is complex and involve alternations in the innate and acquired immune system through cytokines that released by keratinocytes and inflammatory leukocytes contribute to the induction and persistence of inflammatory processes in psoriasis. This study was carried out to evaluate the immunological aspects in psoriasis patients attended consultation clinics of dermatology at Hawler Teaching Hospital in Erbil city/Iraq. Blood samples were obtained from 50 psoriatic patients and 30 healthy controls. Serum neopterin (NPT), tumor necrosis factor-alpha (TNF–α), interleukin-10 (IL–10), interleukin-22 (IL–22), high sensitive C-reactive protein (hsCRP), and malondialdehyde (MDA) levels were estimated in the patients. The result showed that serum TNF-α, IL-22, NPT, hsCRP, and MDA were highly significant in the psoriatic patients compared to healthy controls (p< 0.05), while serum IL-10 showed no significant difference between psoriatic patients and healthy controls. The study revealed that elevation of serum NPT, TNF-α, IL-22, hsCRP, MDA in one hand, and impaired IL-10 expression, on the other hand, are involved in the pathogenesis of psoriasis by induction and maintenance of psoriatic lesion. The dysregulation of IL-10 is associated with enhanced immunopathology and increased risk for chronic non-healing infection in psoriasis patients. Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The immunopathogenesis of this disease is complex and involve alternations in the innate and acquired immune system through cytokines that released by keratinocytes and inflammatory leukocytes contribute to the induction and persistence of inflammatory processes in psoriasis. This study was carried out to evaluate the immunological aspects in psoriasis patients attended consultation clinics of dermatology at Hawler Teaching Hospital in Erbil city/Iraq. Blood samples were obtained from 50 psoriatic patients and 30 healthy controls. Serum neopterin (NPT), tumor necrosis factor-alpha (TNF–α), interleukin-10 (IL–10), interleukin-22 (IL–22), high sensitive C-reactive protein (hsCRP), and malondialdehyde (MDA) levels were estimated in the patients. The result showed that serum TNF-α, IL-22, NPT, hsCRP, and MDA were highly significant in the psoriatic patients compared to healthy controls (p< 0.05), while serum IL-10 showed no significant difference between psoriatic patients and healthy controls. The study revealed that elevation of serum NPT, TNF-α, IL-22, hsCRP, MDA in one hand, and impaired IL-10 expression, on the other hand, are involved in the pathogenesis of psoriasis by induction and maintenance of psoriatic lesion. The dysregulation of IL-10 is associated with enhanced immunopathology and increased risk for chronic non-healing infection in psoriasis patients.

Serum Concentrations of Interferon Gamma (IFN-γ) in Patients with Psoriasis: Correlation with Clinical Type and Severity of the Disease.

Introduction: The etiopathogenesis of psoriasis is still unclear but there is evidence that many of cytokines released by keratinocytes and inflammatory leukocytes may contribute to the induction or persistence of the inflammatory process in psoriasis. Aim: The aim of the study was to evaluate serum concentrations of Interferon gamma (IFN-γ) in patients with psoriasis and the healthy subjects and also to assess a possible association between IFN-γ, clinical type and severity of disease. Material and Methods: The study included a total of 60 patients with psoriasis and 20 healthy subjects in the control group. According to the clinical type of disease, patients with psoriasis were divided into four groups: psoriasis vulgaris (PV), psoriasis erythrodermica (PE), psoriasis pustulosa (PP) and psoriasis arthropatica (PA). Blood samples were collected from all psoriasis patients and from healthy control subjects. Serum IFN-γ levels were measured by an enzyme-linked immunosorbent assay (ELISA) technique. The severity of PV was assessed by Psoriasis Area and Severity Index (PASI) score. Results: The serum concentration of IFN-γ in patients with psoriasis was significantly higher than that in the control group (1.91±1.79 pg/mL vs 0.91±0.38 pg/mL, respectively). Significantly elevated serum IFN-γ concentrations were noticed in patients with PV (2.15±0.30 pg/mL). There was no statistically significant difference between the mean values of IFN- γ compared to the clinical type of psoriasis (p>0.05). In the group of patients with PV 36 (85.71%) patients had mild form of disease with PASI <50, and 6 (14.29%) patients had severe disease with PASI >50. It was not found statistically significant correlation between serum IFN-γ level and PASI score in the group of PV. Conclusions: The results of our study indicate that psoriasis is associated with significant changes in the serum concentration of IFN-γ. There was no significant correlation between serum IFN-γ concentrations, clinical type of psoriasis and severity of PV evaluated with the use of PASI score.

Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson.

Interleukin-17 and interleukin-23 play major roles in the inflammatory process in psoriasis. The Gi protein-associated A3 adenosine receptor (A3AR) is known to be overexpressed in inflammatory cells and in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory conditions. Piclidenoson, a selective agonist at the A3AR, induces robust anti-inflammatory effect in psoriasis patients. In this study, we aimed to explore A3AR expression levels in psoriasis patients and its role in mediating the anti-inflammatory effect of piclidenoson in human keratinocyte cells. A3AR expression levels were evaluated in skin tissue and PBMCs derived from psoriasis patients and healthy subjects. Proliferation assay and the expression of signaling proteins were used to evaluate piclidenoson effect on human keratinocytes (HaCat). High A3AR expression levels were found in a skin biopsy and in PBMCs from psoriasis patients in comparison to healthy subjects. Piclidenoson inhibited the proliferation of HaCat cells through deregulation of the NF-κB signaling pathway, leading to a decrease in interleukin-17 and interleukin-23 expression levels. This effect was counteracted by the specific antagonist MRS 1523. A3AR overexpression in skin and PBMCs of psoriasis patients may be used as a target to inhibit pathological cell proliferation and the production of interleukin-17 and interleukin-23.

The effect of phototherapy on systemic inflammatory process in patients with plaque psoriasis

Psoriasis is a common, chronic immune-mediated inflammatory disease. The inflammatory process in psoriasis has systemic effects and may influence the development of psoriatic comorbidities. The systemic action of phototherapy in patients with psoriasis has been so far poorly elucidated. We aimed to investigate the expression of genes encoding selected psoriasis-related cytokines in peripheral blood mononuclear cells (PBMCs) isolated from patients with psoriasis before and after treatment with phototherapy. 17 patients with mild to moderate plaque psoriasis were treated with narrow band-UVB (NB-UVB), 8 patients with moderate to severe plaque psoriasis with bath-psoralen-ultraviolet A therapy (PUVA). PBMCs were isolated by Ficoll gradient density centrifugation. Expression of genes encoding TNF-α, IL-17A, IL-6, IL-1 β, INF-γ, and IL-10 in PBMCs of patients with psoriasis before and after phototherapy was analyzed with quantitative RT-PCR. Treatment with NB-UVB therapy led to a significant decrease in IL-17A, TNF-α, and IL-6 mRNA levels in PBMCs (p=0.003; p=0.042; p=0.019, respectively). Following treatment with bath-PUVA therapy, we observed a significant decrease in TNF-α and IL-6 mRNA levels in PBMCs (p=0.031, p=0.035, respectively).Treatment with phototherapy in patients with psoriasis may affect systemic inflammation by downregulation of the expression of genes encoding proinflammatory cytokines in PBMCs, implicated in the development of psoriasis and psoriatic comorbidities.

Topical Turmeric Microemulgel in the Management of Plaque Psoriasis; A Clinical Evaluation.

Psoriasis is an autoimmune and recurrent chronic inflammatory skin disease. About 1-3% of the world wide populations are affected. The characteristic features are hyperprolifration of keratinocytes leading to redness, thickening and scaling of epidermis followed with itching and appearance of the lesions which in most cases bother the patients medically and psychologically. Psoriasis is symptomatically treated by the range of oral and topical medications, however, major side effects in some cases are associated with them. Based on several studies, Curcuma longa can inhibit several inflammatory enzymes mainly involved in the inflammatory process of Psoriasis. Therefore, we decided to target this well-known herbal agent with fantastic safety profile to be formulated as a novel topical microemulgel. The clinical and therapeutic benefit of this novel topical formulation was evaluated on 34 patients with mild to moderate plaque psoriasis in a randomized, prospective intra-individual, right-left comparative, placebo-controlled, double-blind clinical trial. The Dermatology Life Quality Index (DLQI) Questionnaire and Psoriasis area & severity index (PASI) score as well as photos before and after treatment was used to evaluate the outcomes. The results show that the clinical and quality of life parameters in treated lesions in comparison with untreated lesions have improved (P<0.05). The reported side effects were also recorded and were trivial. Based on our findings, the proposed microemulgel may well be considered as an alternative in some patients and most likely as an add-on therapeutic option for many patients suffering with plaque psoriasis.

Chemerin and calprotectin levels correlate with disease activity and inflammation markers in psoriasis vulgaris

Psoriasis is a chronic inflammatory dermatosis that affects about 2–3% of the general population. We aimed to investigate the relationship between serum chemerin and calprotectin levels and the inflammatory markers that can lead to oxidative damage. Fifty patients with psoriasis and 30 healthy controls were included in the study. Levels of chemerin and calprotectin were measured in addition to levels of C-reactive protein, the erythrocyte sedimentation rate, and the white blood cell count to evaluate inflammation. According to our findings, chemerin and calprotectin levels in the patient group were significantly higher than in the control group ( p < 0.01 and p < 0.001, respectively). Patients with psoriasis were divided into three groups based on the Psoriasis Area and Severity Index: mild, moderate, and severe. The chemerin levels in the severe and moderate groups were significantly higher than in the mild group ( p < 0.01 and p < 0.05, respectively). The calprotectin levels in the severe psoriasis group were also significantly higher than in the mild group ( p < 0.05). Similarly, the erythrocyte sedimentation rate and levels of fibrinogen and C-reactive protein were significantly higher in patients with psoriasis than in the control group ( p < 0.05, p < 0.01, and p < 0.001, respectively). Stepwise regression analysis was used to assess the individual contributing factors. Among these contributing factors, the chemerin levels were observed to be positively correlated with both the Psoriasis Area and Severity Index ( R 2 = 0.111) and the calprotectin level ( R 2 = 0.445). Calprotectin was observed to be positively correlated with both the C-reactive protein ( R 2 = 0.119) and chemerin levels ( R 2 = 0.315). The chemerin and calprotectin levels in patients with psoriasis showed that there is an inflammatory process in psoriasis and that these markers are useful indicators of the severity of psoriasis.

The potent immunosuppressive role of Interleukin (IL)-37 in the pathogenesis of psoriasis (THER6P.846)

Abstract IL-37 has emerged as a fundamental inhibitor of innate immune response. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells, triggering epidermal hyperplasia, increased inflammatory cells infiltration and high inflammatory mediator production. To research the presumed unique “cooling fires of inflammation” properties of IL-37 in psoriasis, we firstly found that IL-37 was abundantly distributed in human psoriatic plaques (mainly localized in effector memory T cells and macrophages not regulatory T cells). Further, we explored the possible immunomodulatory mechanism of IL-37 in psoriasis models in vitro and in vivo. IL-37 was effective in suppressing the production of chemokines, proinflammatory cytokines and antimicrobial peptides in human keratinocytes which recapitulated numerous features of psoriasis in vitro. IL-37 relieved the psoriatic symptoms of keratin14-VEGF Tg mice (widely-used psoriasis model) including thinner epidermis and diminished lymphocyte infiltration, and greatly dampened Th1 type cytokines production and mast cells recruitment in psoriatic lesions. Our results support the idea that the presence of IL-37 attenuates the inflammatory process in psoriasis by disrupting the linkage between innate immunity and adaptive immune response, indicating a hopeful therapeutic approach for immune-mediated disorders.

IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

IL-37 is a potent inhibitor of innate immunity by shifting the cytokine equilibrium away from excessive inflammation. Psoriasis is thought to be initiated by abnormal interactions between the cutaneous keratinocytes and systemic immune cells, triggering keratinocyte hyperproliferation. In the current study, we assessed IL-37 in two well-known psoriasis models: a human keratinocyte cell line (HaCaT) and the keratin 14 VEGF-A-transgenic mouse model. First, we used the HaCaT cell line, which was transiently transfected with an overexpressing IL-37 vector, and tested the effect of IL-37 on these cells using a mixture of five proinflammatory cytokines. IL-37 was effective in suppressing the production of CXCL8, IL-6, and S100A7, which were highly upregulated by the mixture of five proinflammatory cytokines. Keratin 14 VEGF-A-transgenic mice were treated with plasmid coding human IL-37 sequence-formulated cationic liposomes, and we observed potent immunosuppressive effects over the 18-d period. In this model, we observed reduced systemic IL-10 levels, local IFN-γ gene transcripts, as well as mild mast cell infiltration into the psoriatic lesions of the mice. Immunohistochemical analysis indicated that IL-37 was expressed by effector memory T cells, as well as macrophages, in human psoriatic plaques. In conclusion, our studies strongly indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of both experimental psoriasis models in vitro and in vivo by downregulating proinflammatory cytokines. Importantly, our findings highlight new therapeutic strategies that can be designed to use this immunosuppressive anti-inflammatory cytokine in psoriasis and other inflammatory cutaneous diseases.

High-sensitivity C-reactive protein, lipid profile, malondialdehyde and total antioxidant capacity in psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and lymphocytic infiltration. The ongoing inflammatory process in psoriasis affects the arterial wall promoting the atherosclerotic process, increasing the risk of cardiovascular disease in a younger group of patients. Atherosclerotic processes involve an inflammatory component and high-sensitivity C-reactive protein considered as a marker of the inflammatory component in atherosclerosis. This study was undertaken to evaluate the levels of hsCRP and the traditional risk markers like lipid profile in psoriasis. A case control study as done with 40 cases of psoriasis and 40 healthy controls. The biochemical parameters: lipid profile, hsCRP, malondialdehyde and total antioxidant capacity were estimated on the fasting blood samples. There was a significant increase in lipid profile in cases but these levels were well within the reference ranges for the same. There was a significant rise in hsCRP and malondialdehyde with decreased levels of total antioxidant capacity in cases suggesting a state of inflammation and oxidative stress which co-exists with psoriasis and also plays a role in atherosclerosis. Keywords : Inflammation; atherosclerosis; cardiovascular disease; oxidative stress

Psoriasis and cardiovascular risk factors: A case-control study on inpatients comparing psoriasis to dermatitis

Previous reports demonstrated an association between psoriasis and cardiovascular disease (CVD) risk factors. However, most of these studies were based on computerized databases of outpatient clinics, which, because of International Classification of Diseases, Ninth Revision coding issues, require validation of the diagnosis of psoriasis. We sought to study associations between psoriasis and CVD risk factors among psoriatic inpatients compared to inpatients with dermatitis. A case-control study was performed using computerized medical databases from the Department of Dermatology at Rabin Medical Center in Israel. Inpatients given the diagnosis of psoriasis were compared with inpatients given the diagnosis of forms of dermatitis for the prevalence of smoking, obesity, diabetes, hypertension, hyperlipidemia, and CVD. Logistic regression models were used for multivariate analyses. The study included 1079 inpatients with psoriasis and 1079 age- and gender-matched inpatients with dermatitis (control patients). A multivariate logistic regression model demonstrated that psoriasis is an independent risk factor for diabetes (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.17-1.75), hypertension (OR 1.31; 95% CI 1.09-1.58), obesity (OR 1.32; 95% CI 0.99-1.76), and smoking (OR 1.38; 95% CI 1.10-1.73). Development of CVD was not significantly associated with psoriasis when correcting for diabetes, obesity, and hypertension. Our study group was composed of inpatients only, which may be biased toward more elderly patients with severe psoriasis who may have consumed systemic treatment including immunosuppressants. Our study supports previous reports of an association between psoriasis and CVD risk factors, suggesting that the inflammatory process in psoriasis, but not in dermatitis, may have a systemic impact resulting in development of CVD risk factors.

Effective Therapy with Anti‐TNF‐α in Patients with Psoriatic Arthritis Is Associated with Decreased Levels of Metalloproteinases and Angiogenic Cytokines in the Sera and Skin Lesions

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in sustaining the inflammatory process in the skin as well as in the joints of patients with psoriasis and psoriatic arthritis. In fact, biological therapies based on monoclonal antibodies against TNF-alpha have been proven to be effective on both the arthropathy and the cutaneous symptoms of the disease. Among the several effects produced by TNF-alpha on keratinocytes there is the induction of expression of MMP-9, a matrix metalloproteinase (MMP) produced mainly by monocytes and macrophages. In this article we refer to the results of a study on the behavior of MMP-9 in the sera and in the lesional skin in association with effective therapy with infliximab. Measurements of TNF-alpha, MMP-2, vascular endothelial growth factor (VEGF), and E-selectin were also performed in the same samples. Eleven psoriatic patients included in a therapeutic protocol based on the administration of infliximab monotherapy were collected before treatment and after 6 and 12 weeks of therapy. Significant decrease of MMP-9 and MMP-2 levels in the sera was associated with clinical improvement and with the decrease of TNF-alpha, VEGF, and E-selectin, angiogenic molecules already known to be implicated in the clinical expression of psoriasis. The clinical amelioration of the cutaneous expression of psoriasis was significantly associated with the decrease of MMP-9, TNF-alpha, and E-selectin levels, spontaneously released by lesional biopsy samples before and after therapy, measured in the culture supernatants by immunoenzymatic assays. In addition, significant correlations were found between the clinical score and TNF-alpha, MMP-9, and E-selectin lesional production. MMP-9 levels were significantly correlated with those of TNF-alpha. Our findings show the existence of a direct relationship between MMP-9 and TNF-alpha production, strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis, while a different role may be attributed to MMP-2.

Decreased levels of metalloproteinase-9 and angiogenic factors in skin lesions of patients with psoriatic arthritis after therapy with anti-TNF-α

BackgroundInflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-α plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-α on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-α production.MethodsEleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-α monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-α, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI).ResultsClinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-α (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released by lesional biopsies before and after therapy. In addition, significant correlations were found between the PASI measurements and TNF-α (r2 = 0.33, P = 0.005), MMP-9 (r2 = 0.25, P = 0.017), E-selectin (r2 = 0.24, P = 0.018) production. MMP-9 levels were significantly correlated with those of TNF-α (r2 = 0.30, P = 0.008). A significant decrease of MMP-9 in the sera, associated to the clinical improvement was also found.ConclusionOur findings show the existence of a direct relationship between MMP-9 and TNF-α production strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis.

Interleukin-1: A key inflammatory mediator in psoriasis?

The pro-inflammatory cytokine interleukin-1 (IL-1) is constitutively expressed by keratinocytes in vivo and has been shown to be expressed in psoriatic lesional skin. To determine what role the IL-1 system might contribute to the inflammatory process in psoriasis, semi-quantitative RT-PCR and cRNA microarray studies were performed on biopsies excised from lesional and non-lesional skin. Whilst IL-1α mRNA levels showed a reduction in lesional skin in a subset of patients, steady state IL-1β mRNA was increased markedly. Neither of the two IL-1 receptor transcripts nor total IL-1 receptor antagonist exhibited major changes within the lesion. Expression of the IL-1-induced chemokine IL-8 was only observed in lesional epidermis. Functional genomic experiments comparing transcriptome profiles derived from psoriatic lesional skin and IL-1 stimulated keratinocytes demonstrated a striking level of overlap. Taken together, these data suggest that IL-1 is likely to be an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target.

Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis

A contributing role of neurogenic inflammation has provided a new dimension in understanding the pathogenesis of various cutaneous and systemic inflammatory diseases such as atopic dermatitis, urticaria, rheumatoid arthritis, ulcerative colitis and bronchial asthma. Several critical observations, such as (i) psoriasis resolves at sites of anaesthesia, (ii) neuropeptides are upregulated, and (iii) there is a marked proliferation of terminal cutaneous nerves in psoriatic plaques, encouraged us to search for a mechanism of neural influence in inflammation and inflammatory diseases. In immunohistochemical studies, we found that keratinocytes in lesional and nonlesional psoriatic tissue express high levels of nerve growth factor (NGF) and that there is a marked upregulation of NGF receptors, p75 neurotrophin receptor (p75NTR) and tyrosine kinase A (TrkA), in the terminal cutaneous nerves of psoriatic lesions. As keratinocytes of psoriatic plaques express increased levels of NGF, it is likely that murine nerves will promptly proliferate into the transplanted plaques on a severe combined immunodeficient mouse. Indeed, we have noted marked proliferation of nerve fibers in transplanted psoriatic plaques compared with the few nerves in transplanted normal human skin. By double label immunofluorescence staining, we have further demonstrated that in these terminal cutaneous nerves there is a marked upregulation of neuropeptides, such as substance P and calcitonin gene-related protein. These observations, as well as recent findings about NGF-induced chemokine expression in keratinocytes, further substantiate a role of the NGF-p75NTR-TrkA system in the inflammatory process of psoriasis. Currently, we are evaluating antagonists to selected neuropeptides and NGF/receptors, with the expectation of identifying pharmacological agents to counter neurogenic inflammation in psoriasis.

Upregulation of RANTES in psoriatic keratinocytes: a possible pathogenic mechanism for psoriasis.

Intraepidermal collections of neutrophils and lymphocytes are unique features of the inflammatory reaction of psoriasis. Migration of leukocytes from dermis to the epidermis suggests a role for chemotactic agent(s). In recent years, increased levels of chemokines such as IL-8 , GRO-a and MCP-1 have been reported in the keratinocytes of psoriatic tissue. IL-8 and GRO-alpha belong to a subfamily (C x C) class and MCP-1 is a beta chemokine. In this study, we investigated RANTES, which is a beta chemokine (C-C class); RANTES has been found to be associated with various cell-mediated hypersensitive disorders. We obtained eight skin biopsies from chronic psoriatic plaques, and five biopsies each from non-lesional psoriatic skin, lichen planus, eczematous dermatitis and skin from healthy controls. Snap-frozen samples were cut into 7 microm cryosections and stained with 6 mg/ml of monoclonal anti-RANTES mouse IgG (DNAX, Palo Alto, CA). Standard immunohistochemistry techniques were applied. RANTES was detected only in the keratinocytes. The number of keratinocytes in per mm2 of epidermis stained for RANTES were 116.79+/-98.42 in psoriatic tissues compared to 32.00+/-46.05 (p<0.05), 6.39+/-3.59 (p<0.01), 2.64 +/-1.15 (p<0.01) and 3.53+/-5.26 (p<0.01), respectively, in the non-lesional, lichen planus, eczematous lesions and normal skin. This is the first study to report that the keratinocytes of psoriatic tissue express high levels of RANTES compared to the controls. IL-8 and related molecules (C x C class) are predominantly chemotactic for neutrophils and MCP-1 is a strong chemotactic factor for monocytes. In contrast, RANTES is chemotactic for memory T cells and activated naive T cells. Increased amounts of RANTES as reported here provide an explanation for migration of the activated T cells to the epidermis of the psoriatic lesions. In addition, RANTES activates T cells. These results suggest that RANTES may have a significant role in the inflammatory process of psoriasis. Our findings further substantiate a regulatory role for keratinocytes in the inflammatory process of psoriasis.

Surprisingly high levels of anaphylatoxin C5a des Arg are extractable from psoriatic scales

Water-soluble extracts from psoriatic scales and normal human skin were prepared using either phosphate-buffered saline, pH 7.2, or 0.1 M carbonate buffer, pH 10.8. Anaphylatoxin C5a des Arg was quantified using a novel sandwich enzyme-linked immunosorbent assay (ELISA) using neoepitope-specific monoclonal antibodies. Alkali was about five to eight times more efficient than PBS in extracting C5a des Arg from scales, probably via dissociation of bound C5a des Arg. C5a des Arg concentration in scales from three patients suffering from psoriasis vulgaris varied between 2.5 and 4.6 ng/mg scale. No C5a des Arg was detectable in normal skin extracts. The biological activity of alkali-extractable C5a des Arg, i.e. chemotaxis, was preserved. The concentration of C5a des Arg relative to the concentration of albumin was taken as a parameter of the degree of complement activation in the psoriatic lesions, and was found to be more than six times higher than values attained in serum after maximum complement activation by zymosan. We conclude that complement activation may play a quantitatively important role in the inflammatory process in psoriasis.

Interleukin 1a, Tumor Necrosis Factor a, and Interferon ? in Psoriasis

• Although recent studies have suggested that a variety of cytokines released by keratinocytes and inflammatory leukocytes could contribute to induction or persistence of the inflammatory processes in psoriasis, it remains unclear how production of these cytokines is regulated in psoriatic patients. To elucidate the biologic relevance of these cytokines to the pathogenesis of psoriasis, we investigated serum levels of interleukin 1α, tumor necrosis factor α, and interferon γ in 21 patients with psoriasis vulgaris, together with 21 healthy controls. The mean serum levels of interleukin 1α and tumor necrosis factor α were not significantly different from those in controls, while those of interferon γ were significantly elevated in the patients with psoriasis. Serum levels of interleukin 1α correlated negatively with clinical disease severity expressed as psoriasis area and severity index score and with duration of psoriasis. In contrast, interferon γ levels were related, although not significantly, to disease severity. In addition, an inverse correlation was noted between the interleukin 1α levels and interferon γ levels. These results indicate that interleukin 1α and interferon γ may be relevant to the induction and perpetuation, respectively, of the inflammatory responses in psoriasis, and that these cytokines, which have similar biologic properties, may strictly regulate one another's production in vivo. (Arch Dermatol.1991;127:827-830)