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Biomedical subjects

R W Groves

Publications and source records attributed to R W Groves.

At least 19 recordsLinked to original sources
PubMed2002

Haemorrhage into chronic plaque psoriasis as a consequence of disseminated intravascular coagulation.

We describe a patient with chronic plaque psoriasis who developed haemorrhage into pre-existing lesions during an episode of disseminated intravascular coagulation secondary to sepsis. Disseminated intravascular coagulation is a complex disorder characterized by widespread intravascular deposition of fibrin with consumption of coagulation factors and platelets and occurs as a consequence of many disorders that release procoagulant material into the circulation or cause widespread endothelial damage or platelet aggregation. As both disseminated intravascular coagulation and psoriasis occur relatively frequently in the general population we were surprised to find no previous reports of this phenomenon in the literature.

Chronic Disease↗
PubMed2001

Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice.

Langerhans cell (LC) migration from epidermis to draining lymph node is a critical first step in cutaneous immune responses. Both TNF-alpha and IL-1 beta are important signals governing this process, but the potential regulatory role of IL-1 alpha processing by caspase-1 is unknown. In wild-type (WT) mice, application of the contact allergens 2,4-dinitrofluorobenzine and oxazolone lead to a marked reduction in epidermal LC numbers, but in caspase-1-deficient mice this reduction was not observed. Moreover, although intradermal injection of TNF-alpha (50 ng) induced epidermal LC migration in WT mice, this cytokine failed to induce LC migration in caspase-1-deficient mice. Intradermal IL-1 beta (50 ng) caused a similar reduction in epidermal LC numbers in both WT and caspase-1-deficient mice, indicating that, given an appropriate signal, caspase-1-deficient epidermal LC are capable of migration. Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazolone was inhibited in caspase-1-deficient mice, indicating a functional consequence of the LC migration defect. In organ culture the caspase-1 inhibitor Ac-YVAD-cmk, but not control peptide, potently inhibited the epidermal LC migration that occurs in this system, and reduced spontaneous migration of LC was observed in skin derived from caspase-1-deficient mice. Moreover, Ac-YVAD-cmk applied to BALB/c mouse skin before application of contact sensitizers inhibited LC migration and contact hypersensitivity in vivo. Taken together, these data indicate that caspase-1 may play a central role in the regulation of LC migration and suggest that the activity of this enzyme is amenable to control by specific inhibitors both in vivo and in vitro.

Administration, Cutaneous↗
PubMed2001

Hairy psoriasis.

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Adult↗
PubMed2001

Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism.

Following skin sensitization a proportion of epidermal Langerhans cells (LC) are stimulated to leave the skin and to migrate, via afferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendritic cells (DC). It has been demonstrated previously that tumour necrosis factor-alpha (TNF-alpha), an inducible product of epidermal keratinocytes, and interleukin (IL)-1beta, produced exclusively by LC in murine epidermis, provide important signals for the initiation of this response. Recently, it has been demonstrated that IL-18, a cytokine produced by both LC and keratinocytes within the epidermis, may also participate in immune responses induced following skin sensitization. In the present investigations, the ability of IL-18 to contribute to the regulation of LC migration and the accumulation of DC in draining lymph nodes has been examined. It was found that, like IL-1beta, IL-18 administered intradermally to mice resulted in a significant reduction in epidermal major histocompatibility complex (MHC) class II+ LC densities and a marked increase in lymph node DC numbers. Using neutralizing anti-TNF-alpha and blocking anti-type I IL-1 receptor (IL-1RI) antibodies, it was shown also that the induction by IL-18 of both LC mobilization and DC accumulation in regional lymph nodes was dependent upon availability of TNF-alpha and the integrity of IL-1RI signalling. Furthermore, using IL-1beta converting enzyme (caspase-1) knockout mice, IL-18-induced LC migration was found to have a mandatory requirement for active IL-1beta. Importantly, not only was IL-18 able to contribute to the regulation of LC migration, it was found to be essential for the manifestation of these processes in response to topical sensitization with the contact allergen oxazolone.

Allergens↗
PubMed2000

No apparent effect of cidofovir in epidermodysplasia verruciformis.

This paper reports the failure of a patient suffering from Epidermodysplasia verruciformis, characterised by widespread infection of the skin with human papillomaviruses, to respond to topical and systemic treatment with the antiviral agent, Cidofovir, despite its previously demonstrated effectiveness against a range of different papillomavirus-associated conditions.

Adult↗
PubMed2000

Human keratinocytes constitutively produce but do not process interleukin-18.

BACKGROUND: Interleukin (IL)-18 is a potent immunomodulatory cytokine which promotes T-helper (Th) 1 and cytotoxic responses. IL-18 signals through a two-chain receptor (IL-18R and accessory protein-like subunit, AcPL), and an inhibitory molecule, IL-18 binding protein (IL-18BP), has recently been characterized. OBJECTIVES: The aim of the present study was to define the production of IL-18 and its receptor by human keratinocytes. METHODS: The presence of IL-18 was determined using polymerase chain reaction in human keratinocyte cultures with or without treatment with potential inducers. RESULTS: The IL-18 gene was constitutively transcribed by primary human keratinocytes and cell lines and was not significantly altered following exposure to IL-1 beta, tumour necrosis factor-alpha, interferon (IFN)-gamma, phorbol myristate acetate or nickel sulphate. IL-18 protein was constitutively present at high levels in keratinocyte lysates and was detectable in supernatants exclusively in the unprocessed, 24-kDa form. Cytokine exposure failed to induce any change in protein levels or processing. Primary keratinocytes produced IL-18R and AcPL constitutively at the mRNA level, in addition to low levels of IL-18BP, which was transcriptionally inducible following treatment with IFN-gamma. CONCLUSIONS: These findings demonstrate that IL-18 is constitutively synthesized by human keratinocytes and is released in an unprocessed form in vitro. Release of IL-18 by human keratinocytes may permit them to regulate IFN-gamma production during cutaneous inflammatory responses and suggests that IL-18 may represent an attractive target for immunomodulatory intervention in Th1-mediated inflammatory diseases such as psoriasis.

Cell Culture Techniques↗
PubMed1998

The BB1 monoclonal antibody recognizes both cell surface CD74 (MHC class II-associated invariant chain) as well as B7-1 (CD80), resolving the question regarding a third CD28/CTLA-4 counterreceptor.

The identification of all CD28/CTLA-4 counterreceptors is critical to our understanding of this pivotal pathway of T cell activation. Clouding our understanding has been the reported discrepancies in expression and function of the B7-1 (CD80) molecule based upon the use of the BB1 vs other anti-B7-1 mAbs. To resolve this issue, we have cloned a BB1-binding molecule from the BB1+B7-1(-) NALM-6 pre-B cell line. Here, we demonstrate that this BB1-binding molecule is identical to the cell surface form of CD74 (MHC class II-associated invariant chain). CD74-transfected cells bound the BB1 mAb but not other anti-CD80 mAbs, CD28-Ig, or CTLA4Ig. Absorption and blocking experiments confirmed the reactivity of BB1 mAb with CD74. A region of weak homology was identified between CD74 and the region of B7-1 encoding the BB1 epitope. Therefore, the BB1 mAb binds to a protein distinct from B7-1, and this epitope is also present on the B7-1 protein. Many of the puzzling observations in the literature concerning the expression of human B7-1 are resolved by an understanding that BB1 staining is the summation of CD74 plus B7-1 expression. This observation requires the field to reconsider studies using BB1 mAb in the analysis of CD80 expression and function.

3T3 Cells↗
PubMed1998

Effect of granulocyte macrophage-colony stimulating factor on Langerhans cells in normal and healthy atopic subjects.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a multipotent cytokine produced by many cutaneous cell types including keratinocytes. Langerhans cells (LC) represent the major antigen-presenting cells in skin, and in vitro studies demonstrate that GM-CSF is of pivotal importance in LC. Healthy volunteers (n = 3 non-atopic, n = 3 with atopy) received recombinant human GM-CSF (0. 05 microg/mL) by intradermal injection for 3 days to the same site. Diluent was injected in a similar manner as control. Biopsies were taken 24 h after the final injection and examined immunohistochemically for LC and inflammatory cell markers. Compared with control sites, intradermal GM-CSF resulted in shortening of dendritic cell processes and redistribution of LC in the epidermis; numbers of CD1a + cells in the epidermis were significantly decreased (P < 0.005), while those in the dermis were significantly increased (P < 0.05) following intradermal GM-CSF when compared with controls. Double labelling studies on epidermal CD1a + cells indicated de novo expression of intercellular adhesion molecule (ICAM)-1 and increased expression of HLA-DR following GM-CSF (P < 0. 005, P < 0.005, respectively). Additional findings included a marked mixed inflammatory cell infiltrate in the dermis and increased expression of the endothelial cell adhesion molecules E-selectin and ICAM-1. These data indicate that in normal human skin, GM-CSF induces changes in the phenotype and distribution of CD1a + cells consistent with LC functional maturation and exit from the epidermis to the dermis. As these events are central to the initiation of cutaneous inflammation, GM-CSF may potentially play a critical role in the pathogenesis of inflammatory dermatoses.

Adolescent↗
PubMed1997

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation.

Epidermal keratinocytes can express two types of interleukin 1 (IL-1) receptors: IL-1R1, which is active in signal transduction, and the less well characterized IL-1R2, which is incapable of transducing a signal and can be shed from cells. The binding of IL-1 in solution by IL-1R2 has been demonstrated, and it has been proposed to inhibit IL-1-mediated responses through this mechanism. We and others have reported that keratinocytes can be induced to express IL-1R2 both in vitro and in vivo, often under conditions that also favor IL-1 gene expression. We hypothesized that production of IL-1R2 by keratinocytes would be an efficient means to achieve local inhibition of IL-1-mediated responses without systemic consequences. To test this hypothesis, we have generated transgenic mice that constitutively express IL-1R2 on basal keratinocytes. Keratinocytes cultured from these animals shed the soluble form of the receptor into culture supernatants, and IL-1-inducible production of granulocyte/macrophage colony-stimulating factor was markedly inhibited. In vivo, acute cutaneous vascular leakage, as well as chronic inflammation induced by a well characterized IL-1-dependent stimulus, was significantly inhibited in IL-1R2 transgenic animals. In contrast, contact hypersensitivity was unaffected, suggesting that overexpression of IL-1R2 did not inhibit all types of inflammation globally. Finally, systemic injection of IL-1 induced equivalent levels of plasma IL-6 in IL-1R2 transgenic and nontransgenic mice, suggesting that the activity of the transgenic IL-1R2 remained predominantly local and did not influence systemic IL-1 responses. We conclude that tissue-specific production of IL-1R2 can mediate IL-1 antagonism in tissue microenvironments without systemic consequences. Our transgenic mice may be a useful tool for determining the degree to which different types of cutaneous inflammation depend on the IL-1 system.

Animals↗
PubMed1996

Inflammatory and hyperproliferative skin disease in mice that express elevated levels of the IL-1 receptor (type I) on epidermal keratinocytes. Evidence that IL-1-inducible secondary cytokines produced by keratinocytes in vivo can cause skin disease.

Interleukin (IL)-1 induces a cascade of secondary cytokines in a large number of cell types in vitro, including monocytes, fibroblasts, synovial cells, and keratinocytes. Although it has been proposed that autocrine or paracrine activation of such cells by IL- 1 in situ could orchestrate a local inflammatory response, formal proof for such an hypothesis has been lacking. In an attempt to lower the threshold for secondary cytokine production in these cells in response to IL-1, we have generated transgenic mice (designated IR10) which overexpress functional type 1 IL-1 receptor in basal layer of epidermis keratinocytes. As predicted, keratinocytes from these animals were substantially more responsive to exogenous IL-1 than nontransgenic keratinocytes when stimulated in vitro. When challenged with known inducers of keratinocyte IL-1 synthesis and release, skin of IR10 mice exhibited an exaggerated inflammatory response, characterized by epidermal hyperplasia and an acute dermal inflammatory cell infiltrate. In this setting, the secondary epidermal cytokines gro-alpha and GM-CSF were strongly induced in transgenic epidermis but not in control skin. To confirm that these changes were indeed related to IL-1 mediated activation pathways, IR10 mice were crossed to a distinct line of transgenic mice that overexpress 17-kD IL-l alpha in basal keratinocytes. Double transgenic mice derived from this cross breeding experiment developed spontaneous inflammation of the skin, similar in appearance to that induced by PMA, both histologically and macroscopically, and distinct from that seen in either parental strain spontaneously. Furthermore, secondary cytokines were more strongly induced in the double transgenic than in either parental strain. These findings conclusively demonstrate the potential for functional autocrine pathways of keratinocyte activation mediated by IL-1 alpha in vivo, and suggest that level of expression of type 1 IL-1 receptor may function as a significant control point in physiologic IL-1 mediated autocrine pathways.

Animals↗
PubMed1996

Functional thrombomodulin expression on epithelial skin tumours as a differentiation marker for suprabasal keratinocytes.

In normal human skin,, immunoreactive thrombomodulin (TM) is expressed in a strict differentiation related pattern, solely in suprabasal spinous layer keratinocytes. To evaluate the potential application of TM as a differentiation marker for keratinocyte-derived skin tumours, we have studied immunohistopathological, biochemical and functional TM activities in various skin tumours. Immunoreactive, full sized and enzymatically active TM was expressed in keratinocyte-derived skin tumours (squamous cell carcinoma, seborrhoeic keratosis and partly Bowen's disease), as well as normal epidermal keratinocytes and endothelial cells. However, no TM was detected in basal cell carcinomas, senile keratosis or non-squamous epithelial tumours such as malignant melanoma, naevus pigmentosus and Paget's disease. Interestingly, decreased expression was observed in verruca vulgaris. These findings suggested that differentiation-dependent TM expression was restricted to epithelial skin tumours and undetectable on neural crest derived tumours. TM is a differentiation marker for spinous layer keratinocytes and is a useful tool in histopathological study of epithelial tumours.

Biomarkers, Tumor↗
PubMed1995

Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.

Resting epidermal keratinocytes contain large amounts of interleukin 1 (IL-1), but the function of this cytokine in the skin remains unclear. To further define the role of IL-1 in cutaneous biology, we have generated two lines of transgenic mice (TgIL-1.1 and TgIL-1.2) which overexpress IL-1 alpha in basal keratinocytes. There was high-level tissue-specific expression of transgene mRNA and protein and large quantities of IL-1 alpha were liberated into the circulation from epidermis in both lines. TgIL-1.1 mice, which had the highest level of transgene expression, developed a spontaneous skin disease characterized by hair loss, scaling, and focal inflammatory skin lesions. Histologically, nonlesional skin of these animals was characterized by hyperkeratosis and a dermal mononuclear cell infiltrate of macrophage/monocyte lineage. Inflammatory lesions were marked by a mixed cellular infiltrate, acanthosis, and, in some cases, parakeratosis. These findings confirm the concept of IL-1 as a primary cytokine, release of which is able to initiate and localize an inflammatory reaction. Furthermore, these mice provide the first definitive evidence that inflammatory mediators can be released from the epidermis to enter the systemic circulation and thereby influence, in a paracrine or endocrine fashion, a wide variety of other cell types.

Animals↗
PubMed1995

Inducible expression of type 2 IL-1 receptors by cultured human keratinocytes. Implications for IL-1-mediated processes in epidermis.

Two species of cell surface receptor for IL-1 (IL-1R) have been characterized. Only one of these, the type 1 IL-1R, transduces a signal after ligand binding. Whereas mRNA for the nonsignal transducing type 2 IL-1R seems to have a broad tissue distribution, functional type 2 IL-1R has been carefully studied only in leukocytes and related cell lines. Because normal human keratinocytes, which are IL-1 alpha-producing epithelial cells, inducibly express large numbers of IL-1R, we have studied their putative type 1 and type 2 IL-1R at the level of RNA, protein, and biologic function. At the level of function, gene expression of the IL-1-inducible cytokine granulocyte-macrophage-CSF by keratinocytes was mediated entirely by low numbers of type 1 IL-1R, although type 2 IL-1R were more numerous on both resting and activated keratinocytes. Type I IL-1R mRNA was detected only at very low levels, whereas a marked induction of type 2 IL-1R mRNA was readily observed in activated keratinocytes. A sensitive and specific ELISA demonstrated shed type 2 IL-1R in the conditioned medium of IFN-gamma or PMA-activated keratinocytes. Keratinocyte type 2 IL-1R bound IL-1 alpha with higher affinity (Kd approximately 3 x 10(-9) M) than type 2 IL-1R on leukocytes; however, the intracellular epithelial form of the IL-1R antagonist was bound 100-fold less avidly. These findings demonstrate that a normal nontransformed epithelial cell may express large numbers of the nonsignal transducing type 2 IL-1R that binds IL-1 with high affinity and can be shed into the pericellular environment. This receptor may function as an IL-1 antagonist in autocrine, juxtacrine, and paracrine cutaneous pathways.

Base Sequence↗
PubMed1995

Detection of circulating adhesion molecules in erythrodermic skin disease.

BACKGROUND: Diagnosis of the underlying dermatosis in erythroderma is often difficult. The cause of increased mortality in erythroderma, particularly in relation to infection, is incompletely understood. OBJECTIVE: We investigated the potential diagnostic use of circulating intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and E-selectin (cE-selectin) levels in erythroderma. METHODS: cICAM-1, cVCAM-1, and cE-selectin were measured by enzyme-linked immunosorbent assay in 14 patients with erythroderma of known cause and in 17 control subjects. Levels were correlated with other markers of the inflammatory response. RESULTS: In erythroderma median cICAM-1, cVCAM-1, and cE-selectin levels were significantly elevated, but no difference was found between values in patients with eczema and values in those with psoriasis. Circulating adhesion molecule levels did not correlate with erythrocyte sedimentation rate or total white blood cell count. CONCLUSION: cICAM-1, cVCAM-1, and cE-selectin were detectable in patients with erythroderma but were not differential diagnostic use in this study. Because in vitro these molecules may interfere with normal cell adhesion mechanisms, we speculate that they may contribute to the immunosuppressive state in these patients.

Adult↗