FR255734, a humanized, Fc-Silent, Anti-CD28 antibody, improves psoriasis in the SCID mouse-psoriasis xenograft model

In psoriasis, CD28/B7 costimulatory molecules are well characterized. Here, using the severe combined immunodeficient (SCID) mouse-psoriasis xenograft model, we report therapeutic efficacy of a humanized anti-CD28 monoclonal antibody (FR255734; Astellas Pharmaceuticals Inc., Tokyo, Japan). Transplanted psoriasis plaques on the SCID mouse were treated weekly for 4 weeks with intraperitoneal injections of FR255734 at 10, 3, and 1-mg kg(-1) doses. Groups treated with doses of 10 and 3 mg kg(-1) had significant thinning of the epidermis and reduced HLA-DR-positive lymphocytic infiltrates. The length of the rete pegs changed from 415.2+/-59.6 to 231.4+/-40.4 microm (P<0.005) in the 10-mg kg(-1) group, and from 323.4+/-69.6 to 237.5+/-73.6 microm in the 3-mg kg(-1) group (P=0.002). Positive controls treated with CTLA4-Ig and cyclosporine had significant histological improvement, whereas plaques treated with saline and isotype controls (human and mouse IgG2) remained unchanged. In vitro studies have shown that FR255734 effectively blocked T-cell proliferation and proinflammatory cytokine production. These observations warrant studies to evaluate the efficacy of FR255734 in human autoimmune diseases.     

Nerve growth factor and keratinocytes: a role in psoriasis

Nerve growth factor (NGF) is synthesized and released by human keratinocytes. NGF acts as a neurotrophic molecule at the skin level, as it stimulates the sprouting of nerve fibers and regulates the synthesis and expression of neuropeptides. NGF can thus take part in neurogenic inflammation which in turn is involved in the pathogenesis of several inflammatory dermatoses. Human keratinocytes also synthesize and express the low (p75)-and the high-affinity (trk) NGF-receptor (NGF-R). NGF stimulates keratinocyte proliferation which is blocked by the natural alcaloid K252, a specific inhibitor of trk phosphorylation. K252 inhibits keratinocyte proliferation and induces keratinocyte apoptosis, in the absence of exogenous NGF, indicating the existence of an autocrine loop where NGF and trk act as key players. Finally, NGF protein levels are increased in psoriatic as compared to non-lesional and normal skin, and psoriatic keratinocytes express higher amounts of NGF than normal keratinocytes. This review will discuss the above findings in view of a possible involvement of NGF in the pathomechanisms associated with the development of the psoriatic lesion.     

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.     

Autocrine nerve growth factor in human keratinocytes

Biologically active nerve growth factor (NGF) is synthesised and released by proliferating normal human keratinocytes. NGF up-regulates the expression of NGF mRNA in keratinocytes. Keratinocytes express both the low (p75)- and the high-affinity (TrkA) NGF-receptors, which are located in the basal layer of the epidermis. K252, a specific inhibitor of trk phosphorylation, blocks NGF-induced keratinocyte proliferation, in absence of exogenous NGF. Normal keratinocytes over-expressing TrkA proliferate better than control transfectants, while the NGF mimicking anti-Trk antibody induces an increased keratinocyte proliferation in Trk over-expressing cells as compared to mock transfected keratinocytes. In addition, NGF over-expressing keratinocytes proliferate better than mock transfected cells. K252, by blocking TrkA phosphorylation, induces apoptosis in normal keratinocytes, but not in keratinocytes over-expressing bcl-2. Furthermore, NGF transfected keratinocytes are protected from UV-B-induced keratinocyte apoptosis, by maintaining constant levels of Bcl-2 and Bcl-xL . Taken together these results support the concept of an autocrine survival system sustained by NGF and its high-affinity receptor in human keratinocytes. Because NGF and Trk levels are highly expressed in psoriasis. one could speculate that NGF autocrine system plays a role in the mechanisms associated with this and other hyperproliferative skin conditions, including cancer.     

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

Abstract 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 . Received: 7 December 2000 / Revised: 10 December 2000 / Accepted: 24 February 2001     

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.     

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.     

角质形成细胞生长因子及神经细胞生长因子在银屑病患者皮损中的表达

目的 探讨角质形成细胞生长因子(KGF)及神经细胞生长因子(NGF)与银屑病的关系及银屑病皮损中间质细胞与角质形成细胞的相互作用。方法 应用免疫组化技术分别检测33例银屑病患者皮损、8例非皮损和13例正常人皮肤中KGF、KGF受体、NGF、NGF受体的表达。结果 KGF、KGF受体在银屑病患者基底层和棘细胞下层有极强的表达,与非皮损组及正常对照组间差异有显着性(P<0.05),而非皮损组与正常对照组间差异无显着性(P>0.05).KGF、KGF受体在真皮层未见表达。NGF、NGF受体则主要表达在颗粒层和棘细胞上层,皮损组与非皮损组之间及非皮损组与正常组之间均差异有显着性(P<0.05)。结论 银屑病患者皮损中KGF及NGF可能介导了角质形成细胞的增殖与分化不全;银屑病皮损中存在着间质细胞和角质形成细胞相互作用的紊乱。     

Cellular localization of fractalkine at sites of inflammation: antigen-presenting cells in psoriasis express high levels of fractalkine.

BACKGROUND: Chemokines play a key role in cell trafficking at sites of inflammation. The fractalkine CX3C chemokine is unique in several aspects. Fractalkine is expressed on activated endothelial cells and exists in two forms, either membrane anchored or in a soluble form. The soluble form is a potent chemotactic agent for T cells/monocytes and the anchored form functions as an adhesion molecule. In view of these specific functions fractalkine is capable of controlling the key regulatory mechanisms of cell trafficking at sites of inflammation. OBJECTIVES: Little is known about the significance of this important molecule in inflammatory diseases. We undertook this study to elucidate the role of fractalkine in inflammatory diseases of the skin. METHODS: We used a polyclonal antifractalkine antibody (immunoperoxidase and immunofluorescence stainings) in cryosections obtained from tissues of normal skin and that of selected cutaneous inflammatory diseases (psoriasis, lichen planus, eczema). RESULTS: Increased expression of fractalkine was observed in the dermal blood vessels of lichen planus, eczema and psoriasis tissues. The most striking finding was that the dermal dendrocytes in the papillary dermis of psoriasis tissues expressed high levels of fractalkine. Compared with 186.64 +/- 51.69 fractalkine positive dermal dendrocytes per mm2 of the upper dermis of psoriatic tissue, the number of positive cells in lichen planus, eczema, and normal skin were 17.29 +/- 12.50, 12.50 +/- 6.75 and 5.93 +/- 3.53, respectively. We also performed double label immunofluorescence staining with nerve growth factor receptor (NGF-R) antibody and fractalkine antibody. NGF-R-positive terminal cutaneous nerves were in close contact with the fractalkine-positive dermal dendrocytes in psoriatic lesions. CONCLUSIONS: The results of this study confirm that fractalkine is upregulated at sites of inflammation. Thus, it is likely that this molecule plays a key part in cell trafficking. An increased expression of fractalkine at the dermal papillae provides a plausible explanation for the migration and accumulation of T cells at these sites in psoriasis. Earlier studies have reported an increased number of dermal dendrocytes in psoriatic tissue; however, the functional role of these cells in the pathogenesis of psoriasis is largely unknown. Expression of fractalkine on the surface of dermal dendrocytes suggests an active role for these cells in localization and activation of lesional T cells.     

Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors

BACKGROUND: Although some patients with psoriasis vulgaris also complain of severe pruritus, the data available regarding pruritus in psoriasis are sparse. OBJECTIVES: To clarify the mechanism and mediators involved in the pruritus of psoriasis vulgaris, we compared itch-associated factors in lesional skin from psoriatic patients vs. skin without pruritus quantitatively using a panel of histological and immunohistological parameters. PATIENTS AND METHODS: Biopsied specimens were obtained from 38 patients with psoriasis vulgaris who were divided into two groups according to the presence or absence of pruritus. RESULTS: When compared with psoriatic patients devoid of pruritus, lesional skin from patients with pruritus showed the following characteristic features: (i) a rich innervation both in the epidermis and in the papillary dermis; (ii) an increase in neuropeptide substance P-containing nerve fibres in perivascular areas; (iii) decreased expression of neutral endopeptidase in the epidermal basal layer as well as in the endothelia of blood vessels; (iv) many mast cells showing degranulating processes in the papillary dermis; (v) a strong immunoreactivity for nerve growth factor (NGF) throughout the entire epidermis and an increased NGF content in lesional skin homogenates; (vi) an increase in the expression of high-affinity receptors for NGF (Trk A) in basal keratinocytes and in dermal nerves; (vii) an increased population of interleukin-2-immunoreactive lymphocytes; and (viii) a strong expression of E-selectin on vascular endothelial cells. A significant correlation was observed between the severity of pruritus and protein gene product 9.5-immunoreactive intraepidermal nerve fibres, NGF-immunoreactive keratinocytes, expression of Trk A in the epidermis and the density of immunoreactive vessels for E-selectin. These findings indicate that possible pruritogenic mediators in psoriatic lesional skin are neurogenic factors including innervation, neuropeptide substance P, neuropeptide-degrading enzymes and NGF, activated mast cells, one or more cytokines and endothelial-leucocyte adhesion molecules. CONCLUSIONS: These data document for the first time itch-related local markers in psoriasis, and suggest complex and multifactorial mechanisms of pruritus in the disease. These results provide the groundwork for further studies to evaluate the efficacy of antipruritic treatment for psoriatic patients.     

Reciprocal altered expression of T-cadherin and P-cadherin in psoriasis vulgaris

BACKGROUND: The most characteristic change in psoriasis vulgaris is markedly increased, persistent keratinocyte proliferation. The underlying mechanism of excessive epidermal growth is controversial. We previously found and reported that T-cadherin was expressed in keratinocytes and confined to the basal layer of mouse and human skin. Invasive cutaneous squamous cell carcinoma showed a loss of T-cadherin expression. Another study showed that T-cadherin was a negative growth regulator of epidermal growth factor in T-cadherin transfectant neuroblastoma cells. OBJECTIVES: To obtain insight into the role of T-cadherin in keratinocyte proliferation and to investigate further the pathogenesis of psoriasis vulgaris, we examined the expression of T-cadherin, as well as E- and P-cadherin, in psoriasis vulgaris. METHODS: Four untreated active psoriatic skin samples from psoriasis vulgaris patients and four normal human skin samples from plastic surgery were collected, cryosectioned and immunohistochemically stained by antihuman T-, P- and E-cadherin antibodies. Further, the immunofluorescence intensities of T- and P-cadherin on the basal layer of the epidermis were quantitatively measured by the histogram function of LSM 510 software installed in a Zeiss laser scanning confocal microscope. The data were statistically analysed by Student's t-test. RESULTS: It was observed that T-cadherin was weakly and discontinuously expressed on the basal layer of psoriatic skin, while it was intensively expressed on all basal keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in psoriatic skin samples, although its expression is restricted to the basal cell layer in normal human skin. There were no obvious differences in E-cadherin expression between normal human skin and psoriatic skin. Statistical analyses showed that the immunofluorescence intensity of T-cadherin in the basal cell layer of psoriatic skin (35 +/- 9.08) was significantly decreased compared with that in normal human skin (131.75 +/- 3.49, P = 2.46 x 10(-6)). There was a significant increase (P = 0.00139) in the immunofluorescence intensity of P-cadherin in the basal layer of psoriatic skin (68.25 +/- 12.13) compared with normal human skin (26 +/- 4.90). CONCLUSIONS: The present study demonstrates that there is downregulation of T-cadherin expression and upregulation of P-cadherin expression in psoriatic skin, which are considered to be involved in the hyperproliferation of keratinocytes in psoriasis vulgaris.     

Nerve growth and expression of receptors for nerve growth factor in tumors of melanocyte origin.

Nerve growth factor (NGF) stimulates growth and differentiation of sensory and sympathetic neurons. It is not known what role NGF plays in melanoma development, but nevus and malignant melanoma cells express NGF-receptor (NGF-R). We counted nerve fibers within melanocytic nevi, primary cutaneous melanomas, and cutaneous melanoma metastases using a monoclonal antibody (MoAb) as marker against a 200-kD glycoprotein that is expressed on human nerves. The expression of NGF-R was studied in serial cryostat sections using a MoAb against the NGF-R. Compared to normal skin, increased numbers of nerve fibers were found in 72 melanocytic nevi. In congenital nevi their number significantly increased with age. In 47 primary cutaneous melanomas the number of nerve fibers decreased in proportion to tumor thickness. In 33 cutaneous melanoma metastases no accumulation of nerve fibers was found. NGF-R was not expressed in normal skin melanocytes and in the majority of nevus cells in melanocytic nevi. Considerable numbers of NGF-R-positive nervus cells were found only in some congenital nevi and few acquired nevi with dysplastic features. By contrast, in primary and metastatic melanomas higher expression of NGF-R was observed. The increased number of nerve fibers in melanocytic nevi suggests that neurite-promoting factors are produced in situ. Production of such factors appears to be lost in malignant melanoma cells. The finding of an inverse correlation between an abundance of nerve fibers in NGF-R-poor nevi and a high expression of NGF-R in melanomas that show no evidence of nerve growth suggest a role of NGF and its receptor in malignant melanocytic tumors.     

Activation of dendritic antigen-presenting cells expressing common heat shock protein receptor CD91 during induction of psoriasis

BACKGROUND: Psoriasis is a common and chronic relapsing inflammatory skin disorder. Although a role for T cells in mediating the induction and maintenance of psoriatic lesions is well established, mechanisms responsible for activation of T cells by antigen-presenting cells (APCs) during disease relapse are poorly understood. OBJECTIVES: (i) To determine whether expression of the common heat shock protein (HSP) receptor CD91 correlated with development of psoriasis in a mouse model of psoriasis, (ii) to characterize the lesional cells on which CD91 was expressed, and (iii) to investigate whether CD91+ cells in psoriasis showed signs of activation. METHODS: Two systems were used in order to study the above-mentioned objectives: (i) skin biopsies taken directly from patients with psoriasis (either psoriatic plaques or symptomless prepsoriatic skin) or from healthy donors, respectively, or (ii) (human) skin biopsies collected during development of psoriasis using a novel xenograft mouse model of psoriasis. The skin samples were then either processed for analysis by light microscopy, or labelled with fluorochrome-conjugated antibodies and analysed by confocal laser scanning microscopy. RESULTS: We observed a markedly increased number of CD91+ cells which paralleled development of new psoriatic lesions in the psoriasis mouse model and in established psoriatic plaques compared with symptomless prepsoriatic or healthy skin. Morphology as well as cell-specific markers showed that CD91 was predominantly expressed by dermal dendritic APCs characterized by activation of nuclear factor-kappaB signalling and the presence of tumour necrosis factor-alpha, an important proinflammatory cytokine in the immunopathogenesis of psoriasis. In addition, HSP70, a ligand for CD91, was increased in keratinocytes in close vicinity to CD91-bearing APCs in psoriatic lesions. CONCLUSIONS: These findings indicate massive presence of CD91+ dendritic cells juxtaposed to lesional keratinocytes expressing HSP70, and suggest a novel pathophysiological pathway and therapeutic target for this chronic inflammatory skin disease.     

Neuropeptides and their receptors in psoriatic skin in relation to pruritus

BACKGROUND: Pruritus in patients with psoriasis has been reported to be more common than previously thought. OBJECTIVES: To determine the actual prevalence of pruritus in psoriasis according to severity of psoriasis and to verify the hypothesis of involvement of neuropeptides and their receptors in psoriatic pruritus. METHODS: We analysed questionnaire replies from 152 patients with chronic plaque-type psoriasis and we assayed the expression of neuropeptides and their receptors in lesional skin biopsies obtained from psoriatic patients with pruritus compared with those from psoriatic patients without pruritus, nonlesional skin of patients with pruritic psoriasis and normal controls by confocal laser scanning microscopy. RESULTS: Of the 152 patients with psoriasis, 112 (73.7%) had pruritus, and these patients had a higher mean Psoriasis Area and Severity Index (PASI) score than psoriatic patients without pruritus. There was positive correlation between the PASI score and the intensity of pruritus. Keratinocytes in the psoriatic plaques of patients with pruritus showed consistently increased expression of substance P receptor (SPR), high-affinity nerve growth factor receptor (TrkA) and calcitonin gene-related peptide receptor (CGRPR). CONCLUSIONS: Pruritus is a common feature in psoriasis. Considering the well-known roles of neuropeptides in pathogenesis of both psoriasis and pruritus, increased SPR, TrkA and CGRPR may be involved in the pathogenesis of pruritus in psoriasis and in the severity of psoriasis.     

Cyclosporine in psoriasis treatment. Inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor alpha/epidermal growth factor receptor pathways.

Cyclosporine, an immunosuppressive drug, is effective in the treatment of recalcitrant psoriasis. Previous work suggested that keratinocyte hyperproliferation and inflammation are linked in psoriasis and that immune mechanisms participate in the pathogenesis of psoriasis. Transforming growth factor (TGF) alpha may be an important regulatory factor of epidermal growth as overproduction of TGF-alpha is associated with epidermal hyperplasia in psoriatic plaques and epidermal growth factor receptors are overexpressed in psoriatic epithelium. In this study, the effects of cyclosporine on cultured human keratinocytes were examined. Cyclosporine specifically inhibited keratinocyte cell-cycle progression in the G1 phase without causing keratinocytes to terminally differentiate. Cyclosporine did not decrease the expression of TGF-alpha or epidermal growth factor receptors. These results suggest that the effects of cyclosporine on psoriatic skin are unrelated to direct effects on autocrine growth regulation of keratinocytes via TGF-alpha production or of epidermal growth factor receptor modulation.     

CD109 release from the cell surface in human keratinocytes regulates TGF-β receptor expression, TGF-β signalling and STAT3 activation: relevance to psoriasis

Transforming growth factor (TGF)-β is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-β signalling has been reported in psoriasis, where despite increased expression of TGF-β, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-β signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-β signalling and TGF-β receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl-2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-β receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-β receptor downregulation and decrease in TGF-β signalling in psoriasis.     

Immunologic mechanisms in psoriasis

The demonstration of activated T lymphocytes, HLA-DR+, I-CAM1+, gamma IP-10+ keratinocytes, and increased levels of lymphokines in active plaques suggests that immunologic mechanisms may play a role in the pathogenesis of psoriasis. Epidermal hyperplasia and inflammation in psoriasis may be linked by those cytokines many of which are produced by both keratinocytes and leukocytes. Epidermal acanthosis and keratinocyte mitoses have been observed in delayed-type hypersensitivity reactions and after the intradermal injection of gamma interferon. Gamma interferon and its induced proteins have been demonstrated in active psoriatic plaques. Increased levels of the keratinocyte autocrine cytokines, transforming growth factor (TGF)-alpha and interleukin (IL)-6, have been detected in active plaques. The apparent overexpression of IL-6 in hyperplastic psoriatic tissue may explain features of psoriasis that link keratinocyte proliferation with immune activation and tissue inflammation. Both IL-6 and gamma interferon increased TGF-alpha expression in normal cultured keratinocytes. Cytokines produced during immune activation and other inflammatory processes may lead to epidermal hyperplasia.