IL-17 and IL-17R: an auspicious therapeutic target for psoriatic disease.

The continuous discovery of new T cell subpopulations in human autoimmune diseases is making the immunopathological network more complex. Th17 cells are one such newly identified subset of T cells, characterized by the production of signature cytokine IL-17. In last few years, several studies have strongly established the regulatory role of Th17 cells and its signature cytokine IL-17 in autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. Psoriasis and PsA are immune mediated hyperproliferative diseases, affecting skin and joint respectively. Before the discovery of Th17 cells, psoriasis and psoriatic diseases were thought to be chiefly Th1 mediated diseases; later on IL-17 knockout animal studies as well as human experimental data indicate the crucial role of Th17 cells and its signature cytokine IL-17 in the pathogenesis of these diseases. In vitro human studies have shown the abundance of Th17 cells in the psoriatic plaques. Subsequently our research group has extended this observation in psoriatic arthritis and found the abundance of CD4+IL-17+ T cells in the synovial fluid and majority of these T cells are of memory phenotype (CD4RO+CD45RA-CD11a+). In addition, we showed the significant presence of functional IL-17 receptor in synovial fibroblast of psoriatic arthritis patients. Considering the strong association of IL-17 and psoriatic disease, IL-17 targeted therapy have shown promises in preclinical and clinical trials. In this review article, we have discussed the pathogenic role of IL-17 in psoriatic disease and summarized the therapeutic efficacy and safety profile of different anti IL-17 therapy as an anti-psoriatic agent.

The regulatory role of nerve growth factor and its receptor system in fibroblast-like synovial cells.

OBJECTIVES: Investigating the role of nerve growth factor (NGF) and its receptors (NGF-R) in inflammatory diseases is an active field of research. Inflammatory diseases of the joint are the commonest cause of human morbidity but very little is known about the effect of NGF on synovial tissue biology. Here we have studied NGF/NGF-R and their functional significance on cultured fibroblast-like synovial cells (FLS) collected from the synovial tissue of five healthy subjects. METHODS: NGF/NGF-R expression was determined in the basal condition and after stimulation with tumour necrosis factor (TNF)alpha and interleukin (IL)-1beta by enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS). Proliferation studies were performed by cell count, hexosaminidase assay, and the MTT assay. The synovial fluid (SF) NGF level was studied by ELISA in 12 psoriatic arthritis (PsA), 14 rheumatoid arthritis (RA), and 10 osteoarthritis (OA) patients. RESULTS: FACS studies showed that unstimulated FLS expressed low levels of NGF and the high-affinity NGF-tyrosine kinase receptor TrkA, and TNFalpha and IL-1beta increased NGF and TrkA expression in FLS. NGF (100 ng/mL) increased FLS proliferation by 400% compared to the control (medium only). The NGF level was significantly higher in the PsA group (365.5+/-85.2 pg/mL) than in the RA (120+/-35 pg/mL) and OA groups (30+/-6 pg/mL). CONCLUSIONS: Upregulation of NGF/TrkA in proinflammatory cytokine-activated FLS, the mitogenic effect of NGF on FLS, and the increased NGF level in SF of inflammatory arthritis suggest that there is cross-talk between NGF/NGF-R and FLS. These results also suggest that dysregulated production of NGF may lead to synovial cell proliferation and thus could influence the inflammatory and proliferative cascades of inflammatory arthritis.

Mast cell density and IL-8 expression in nonlesional and lesional psoriatic skin.

BACKGROUND: An important cellular aberration at sites of psoriatic inflammation is an increase in the number of dermal mast cells. Being multifactorial immune effector cells, it is believed that mast cells play an essential role in perpetuating the inflammatory process of psoriasis. However, factors responsible for the infiltration and accumulation of mast cells in psoriatic lesions are largely unknown. Recent studies have demonstrated that Interleukin-8 (IL-8) exerts strong chemotactic effects on mast cells in vitro. Overexpression of IL-8 has also been reported in psoriatic lesions. In this study, we have found a correlation between the expression of IL-8 and dermal mast cell density in lesional psoriatic skin as compared to nonlesional psoriatic skin. METHODS: Four-mm punch biopsies were taken from 14 psoriatic patients and eight healthy volunteers. Using immunohistochemical techniques, 8 microm sections of lesional psoriatic, nonlesional psoriatic, and normal control samples were evaluated for dermal mast cell density and the density of IL-8 expressing keratinocytes. RESULTS: It was found that dermal mast cell density in lesional psoriatic, nonlesional psoriatic, and normal skin was 105.4 +/- 71.2, 42.3 +/- 30.1, and 47.5 +/- 32.5 mast cells/mm(2), respectively. IL-8+ keratinocyte density in lesional psoriatic, non lesional psoriatic, and normal skin was 171.5 +/- 67.1, 25.4 +/- 14.9 and 20.6 +/- 8.7 IL-8+ Keratinocytes/mm(2), respectively. CONCLUSIONS: The results of this study suggest that increased levels of IL-8 in the keratinocytes of psoriatic plaques play a contributing role in the migration of mast cells to lesion sites.

Effect of nerve growth factor on endothelial cell biology: proliferation and adherence molecule expression on human dermal microvascular endothelial cells.

In addition to its effect on the central nervous system, nerve growth factor (NGF) appears to play a key role in the initiation and maintenance of inflammation in many organs. NGF degranulates mast cells, recruits inflammatory cellular infiltrates and activates T cells. Extravascular migration of leukocytes is initially controlled by the interaction of cell surface adhesion molecules of leukocytes and endothelial cells. A marked upregulation of NGF in keratinocytes is also observed in conditions characterized by angiogenesis such as psoriasis and wound healing. In this study we investigated the role of NGF in inflammation by studying its effects on endothelial cell proliferation and intracellular adhesion molecule expression by endothelial cells. The effect of NGF on human dermal microvascular endothelial cell (HDMEC) proliferation was measured using the hexosaminidase assay. ICAM-1 expression on HDMEC was measured by ELISA. The function of ICAM-1 was assessed by adherence of peripheral blood mononuclear cells (PBMC) to HDMEC using 51Cr-labeled PBMC. There was a significant increase in proliferation of HDMEC stimulated with NGF as compared to unstimulated HDMEC (P < 0.001). NGF-neutralizing antibody decreased the mitogenic effect of NGF significantly (P < 0.05). NGF also increased ICAM expression on HDMEC as compared to unstimulated HDMEC (P < 0.05). NGF-neutralizing antibody decreased ICAM expression on NGF-stimulated HDMEC (P < 0.05). The percentage of PBMC adherence was higher in NGF-stimulated HDMEC (P < 0.001). Anti-ICAM antibody decreased PBMC adherence. In the study reported here, the role of NGF in two important aspects of inflammation, i.e. angiogenesis and inflammatory cell recruitment at the site of inflammation, was investigated.

Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation.

Elucidation of the molecular and cellular mechanisms responsible for the pathogenesis of psoriasis had been significantly handicapped due to lack of an ideal animal model. To overcome this hurdle several investigators have developed a number of animal models for psoriasis. Recent establishment of the SCID-human skin chimeras with transplanted psoriasis plaques has opened new vistas to study the molecular complexities involved in psoriasis. This model also offers a unique opportunity to investigate various key biological events such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. The SCID mouse model will be of immense help to target the cellular and molecular events associated with these pathogenic processes and develop novel drugs for psoriasis and other inflammatory diseases. In this article we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.

Role of nerve growth factor in RANTES expression by keratinocytes.

A role of neurogenic inflammation induced by the neuropeptides and nerve growth factor (NGF) has been attributed to the pathogenesis of several cutaneous disorders such as psoriasis, wound healing and eczematous dermatitis. The underlying mechanisms of the inflammatory process induced by NGF are not clearly established. This study explored whether NGF influences the inflammatory process by inducing chemokines. The effects of NGF were investigated on induction of 2 important chemokines, interleukin-8 and RANTES, which are known to be upregulated in the keratinocytes of various inflammatory conditions. NGF significantly increased RANTES production by the keratinocytes (p < 0.001, 2-tailed Student's t-test). Induction of RANTES expression in the keratinocytes by NGF provides further insight regarding the role of NGF-NGF receptor system in cutaneous inflammatory conditions.

Immunomodulatory effects of peptide T on Th 1/Th 2 cytokines.

Peptide T is an octapeptide from the V2 region of HIV-1 gp120. It has been shown to resolve psoriatic lesions--an inflammatory skin disease. The mechanisms of anti-inflammatory actions of peptide T are not well understood. Th1 cytokines such as IL-2, and IFN-gamma are upregulated in psoriasis. These cytokines play a key role in the inflammatory and proliferative processes of psoriasis. The effects of peptide T on Th1 and Th2 cytokines were studied in order to elucidate the mechanisms of antiinflammatory actions of peptide T. It was observed that peptide T at 10(-8) M induces IL-10 production by the human Th2 cell line and PBMC (P < 0.05, ANOVA). Also peptide T at 10(-9) M concentration significantly inhibited IFN-gamma production by PBMC (P < 0.001, ANOVA). Anti IL-10 antibody inhibited the anti-IFN-gamma effect of peptide T (P < 0.05, t-test). Our study shows that peptide T induces IL-10 production and inhibits IFN-gamma production. IL-10 is a potent anti-inflammatory cytokine. It inhibits IL-2 and IFN-gamma production from the T cells and downregulates the expression of TNF-alpha in the antigen presenting cells. Recently, IL-10 has been shown to resolve psoriatic lesions. The effects of peptide T on IL-10 and IFN-gamma production provides a plausible explanation for its clinical efficacy in psoriasis.

Anti-chemotactic activities of peptide-T: a possible mechanism of actions for its therapeutic effects on psoriasis.

Peptide T is an octapeptide (ASTTTNYT) from the V2 region of gpl20 of HIV. D-[Ala]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-amide (DAPTA) is one of its analogue. DAPTA has been shown to resolve the psoriatic lesions. The mechanisms of action of peptide T for its therapeutic effect is not clearly understood. Lymphomononuclear cells play an important roles in inflammatory disease processes. Intraepidermal collection of lymphocytes is a unique feature of the inflammatory processes of psoriasis. It is believed that chemokine such as RANTES (C-C class) plays an important role for intraepidermal localization of the inflammatory infiltrates in psoriasis. In order to study the mechanisms, we have analyzed the effects of DAPTA on monocyte and lymphocyte chemotaxis. Chemotaxis of cells was measured by using Boyden chamber. DAPTA inhibited significantly the monocyte and lymphocyte chemotactic activity of RANTES (p < 0.005, < 0.001). Antichemotactic activities of peptide T analogue could be a possible explanation for its therapeutic efficacy in psoriasis.

Revisit to Kaposi's varicelliform eruption: role of IL-4.

BACKGROUND: Kaposi's varicelliform eruption (KVE) is characterized by disseminated cutaneous eruptions usually caused by infection with herpes simplex virus (HSV). Kaposi's varicelliform eruption is commonly observed among patients with atopic dermatitis (AD). Why AD patients are prone to HSV infections is still an enigma. Recent findings suggest that an increased number of IL-4-secreting cells can be cloned from lesions of AD. Because IL-4 is a known Th1 cell inhibitor, theoretically, by inhibiting the Th1 cells, it could downregulate the immune response against HSV. In this study, we have evaluated the role of IL-4 on HSV replication. METHODS: Peripheral blood mononuclear cells (PBMC) from 10 HSV seronegative and five seropositive healthy individuals were stimulated with PHA, recall antigen (tetanus toxoid), and HSV antigen in combination with IL-4 and anti-IL-4. Supernatants were assessed for interferon (IFN) gamma, IL-4 by enzyme-linked immunosorbent assay (ELISA), and for anti-HSV effect. Anti-HSV effect was assessed by measuring inhibition of the cytopathic effect (CPE) of HSV on a Vero cell line. RESULTS: Both seropositive and seronegative groups showed significant inhibition of IFN-gamma secretion with addition of IL-4 (P < .001, Wilcoxon rank sum test) and this effect could be neutralized by anti-IL-4. There was a direct relationship between the IFN-gamma concentration and the HSV cytopathic effect and an inverse relationship between IL-4 concentration and HSV CPE: CONCLUSIONS: This study provides evidence that IL-4 can enhance HSV infection. Therefore, it is conceivable that patients with conditions of increased activity of IL-4, as in AD, would be prone to extensive forms of HSV infection.