Gamma-interferon inhibits extracellular matrix synthesis and remodeling in collagen lattice cultures of normal and scleroderma skin fibroblasts.

Three-dimensional collagen lattice cultures of fibroblasts mimic the in vivo situation better than monolayer cultures. Here, skin fibroblasts from scleroderma patients and healthy controls were cultivated in collagen lattices, and the effects of recombinant human gamma-interferon (IFN-gamma) on these cultures investigated. IFN-gamma inhibited collagen lattice retraction in a dose-dependent way at concentrations ranging from 10 to 10,000 U/ml. This effect was independent of any alteration to the cell proliferation within the lattices. The inhibition was of the same order of magnitude in normal and pathological fibroblasts. The synthesis of collagen and non-collagen proteins, particularly fibronectin, was increased in scleroderma cultures. It was inhibited in both normal and scleroderma fibroblasts by IFN-gamma, with a maximal effect at the concentration 1000 U/ml, but the inhibition of protein synthesis was far more intense in scleroderma than in normal cells. In situ hybridization, Northern blot and dot blot analyses showed that mRNA coding for pro alpha 1(I) collagen was decreased in IFN-gamma-treated cells, indicating an effect at the pretranslational level. IFN-gamma also inhibited glycosaminoglycan synthesis, but in scleroderma cells only. This study shows that IFN-gamma regulates cell behavior in three-dimensional collagen matrices: (i) it decreases protein and specifically glycosaminoglycan synthesis in scleroderma fibroblasts, (ii) it modulates the interactions between cells and matrix that lead to the retraction of the lattice. Whereas collagen synthesis is largely decreased in lattice cultures like in vivo, it remains increased in the case of scleroderma compared to normal fibroblasts and may be down-regulated by IFN-gamma. Similar conclusions may be drawn for fibronectin and glycosaminoglycans. The inhibitory effect of IFN-gamma on the retraction capacity of fibroblasts and on their ability to synthesize increased amounts of extracellular matrix macromolecules may be of potential interest for therapeutic use of IFN-gamma in scleroderma patients.

Antagonistic effects of interferon-gamma and interleukin-4 on fibroblast cultures.

A major characteristic of scleroderma (SSc) fibroblasts is an increased biosynthesis of extracellular matrix macromolecules that could be linked to impaired regulation by cytokines. We investigated the effects of two cytokines from T lymphocytes, interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), on normal and scleroderma fibroblast cultures. In both types of fibroblasts, IL-4 strongly stimulated collagen synthesis, whereas IFN-gamma was a potent inhibitor. The effects of these cytokines were localized at the pre-translational level, and both mRNA steady-state level and protein synthesis were equally affected. SSc fibroblasts responded to IL-4 and IFN-gamma as well as normal fibroblasts. When fibroblasts were incubated with combinations of both cytokines, IFN-gamma completely suppressed the stimulation of collagen gene expression induced by IL-4. Northern blot and western blot analyses demonstrated that IFN-gamma induced a rapid and strong decrease in the expression of the IL-4 receptor-alpha by fibroblasts. This effect might explain the antagonistic effects of IFN-gamma on the IL-4-dependent enhancement of collagen synthesis. Thus, our data suggest that the alteration of collagen production in scleroderma fibroblasts does not depend on an altered sensitivity of these cells to stimulatory or inhibitory cytokines but is more likely the consequence of an imbalance in the local production of autocrine or paracrine regulatory factors.

Alteration of matrix macromolecule synthesis by fibroblasts from a patient with pachydermoperiostosis.

Pachydermoperiostosis (primary hypertrophic osteoarthropathy) is a very rare genetic disease characterized by pachydermia, periostosis, arthralgia, and finger clubbing. Its pathophysiology is still unclear, but previous studies have reported connective tissue hypertrophy in the skin of these patients. We investigated the synthesis of collagen, fibronectin, and proteoglycans by fibroblasts from affected and unaffected skin from one patient with pachydermoperiostosis and four normal donors. We found that collagen synthesis was largely decreased in fibroblasts from the diseased skin, whereas the synthesis of the small dermatan-sulfate-containing proteoglycan decorin strongly increased. Fibroblasts from the unaffected skin of the patient exhibited syntheses of these macromolecules similar to control fibroblasts from healthy donors. Northern blot and dot blot analyses showed decreased pro alpha 1 (I) collagen in patient's affected and unaffected skin fibroblasts whereas increased decorin mRNA levels were found in fibroblasts from the patient's affected skin. No change in cell proliferation was observed. These data demonstrate an alteration of fibroblast biosynthetic activity in the skin lesions of pachydermoperiostosis, which may be responsible, at least in part, for the patient's phenotype.

Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis.

BACKGROUND: Scleroderma (systemic sclerosis) is a fibrotic disease characterized by an uncontrolled tissular accumulation of collagen. Several cytokines have been implicated in the fibroblast activation leading to fibrosis. For instance, we have previously demonstrated that interleukin-4 (IL-4) is a potent activator of collagen synthesis in fibroblast cultures. In this study, using immunocytochemical methods and in situ hybridization, we investigated the expression of IL-4 in normal and scleroderma skin and fibroblast cultures. OBSERVATIONS: Immunocytochemical studies with anti-IL-4 antibody were performed on biopsy specimens from 9 patients with normal skin and 11 patients with scleroderma. The label was intense or strong in 8 of the 11 scleroderma skin specimens, whereas it was negative or faint in 8 of the 9 normal skin specimens (P < .01). In situ hybridization demonstrated a significant increase of the number of IL-4 messenger RNA grains in scleroderma skin compared with normal skin (3.1 +/- 1.5 [mean +/- SD] vs 0.8 +/- 0.7; P < .001). A strongly positive labeling with the anti-IL-4 antibody was found in the 4 scleroderma fibroblast cultures, whereas it was negative in the 5 fibroblast control cultures (P < .05). CONCLUSIONS: Our results demonstrate that IL-4 is strongly expressed in the dermis of a large majority of patients with scleroderma and might be synthesized by scleroderma fibroblasts. We suggest that IL-4 is one of the cytokines implicated in the early steps of the fibrotic process.

[Acute febrile pustular and bullous neutrophilic dermatosis (Sweet syndrome) disclosing acute myeloblastic leukemia]. / Dermatose neutrophilique aiguë fébrile pustuleuse et bulleuse (syndrome de Sweet) révélant une leucémie aiguë myéloblastique.

We report a patient with Sweet's syndrome (acute febrile neutrophilic dermatosis) revealing an acute myelogenous leukemia. About 10% of Sweet's syndromes are associated with a malignant disease that they can reveal. Among those, hemopathies are the most frequent, and 42% are myelogenous leukemia. These observations emphasize the particular clinical aspects of the Sweet's syndrome associated with an hemopathy.

[Unilateral gustatory flushing syndrome in a child]. / Syndrome des flushs gustatifs unilatéraux de l'enfant.

BACKGROUND: Auriculo-temporal syndrome is rarely seen in children: it is sometimes considered as secondary to an obstetrical injury. CASE REPORT: A 2.5 year-old boy was examined because he suffered from post-prandial flushing of the right cheek for 2 years. He was born normally and neurologic examination was normal. The rash was not associated with sweating or tearing. CONCLUSION: There is no evidence to support food allergy in this case: rather, this syndrome probably occurs in response to salivation.

[Vulvar lymphangiectasis 14 years after treatment for epidermoid carcinoma of the cervix. Treatment with cryosurgery]. / Lymphangiectasies vulvaires 14 ans après le traitement d'un carcinome épidermoïde du col utérin. Traitement par cryochirurgie.

INTRODUCTION: Lymphangiectasia are different from lymphangioma because they arise following damage to the deeper lymphatic vessels. No clinical or histological features are known to distinguish lymphangioma from lymphangiectasia. CASE REPORT: We report a case of vulvar lymphangiectasia occurring 14 years after therapy of squamous carcinoma of the cervix (surgery and post-operative radiotherapy). Our treatment was cryosurgery. DISCUSSION: We analysed the 12 case reports of vulvar lymphangiectasia in the literature, emphasizing misleading clinical aspect of the warty lesions and the risk of repeated infection justifying an appropriate treatment. We propose cryosurgery which provides real benefits with a minimal trauma.

[Cutaneous metastases of melanoma localized on the cicatrix at the site of flap taking]. / Métastases cutanées de mélanome situées sur une cicatrice de prise de greffe.

INTRODUCTION: We report one case of melanoma cutaneous metastases strictly localized on a skin graft donor site distant from the tumor site. CASE REPORT: A patient with a shoulder melanoma was treated by surgery. A split-thickness skin graft was taken from a thigh to cover the raw area. Six months later, nodular cutaneous metastases strictly localized on the skin graft donor site appeared. COMMENTS: Physiopathology of those lesions is unknown. Hyaluronic acid is increased in granulation tissue and could be chimiotactic for melanoma cells.

[Multiple isolated cutaneous myxomas]. / Myxomes cutanés multiples isolés.

INTRODUCTION: Cutaneous myxomas are rare. They are more often single; when they are multiple, they may be one of the component of the Carney's syndrome. CASE REPORT: We report a case of multiple and isolated cutaneous myxomas arising at 19 year-old. Diagnosis was confirmed by histologic studies. Examination failed to reveal other cutaneous or visceral features. DISCUSSION: The multiplicity of cutaneous myxomas is an essential element for diagnosis of Carney's syndrome; other components and notably atrial myxomas can appeared over time. Normal visceral explorations don't eliminated the diagnosis, and follow-up including screening echocardiography must be ensured before concluding, as in our case, as multiple and isolated cutaneous myxomas.

[Bazex paraneoplastic acrokeratosis. Treatment with acitretin]. / Acrokératose paranéoplasique de Bazex. Traitement par acitrétine.

INTRODUCTION: Bazex paraneoplastic acrokeratosis remains a therapeutic challenge when the cancer cannot be treated. We report the third patient in which a complete clearance of the lesions was obtained with oral acitretine. CASE REPORT: A 67 year-old patient had Bazex paraneoplastic acrokeratosis. Despite a complete cancer screening, no cancer was found. A cervical lymph node metastasis was treated with surgery and radiotherapy. Because the cutaneous lesions got worse after this treatment, the patient received oral acitretine. A complete clearing of the lesions was observed within 2 months. DISCUSSION: Only 2 similar cases have been reported to our knowledge. The comparison with these 2 cases supports the efficacy of oral retinoids in this disease. The search and the treatment of the cancer remain compulsory. CONCLUSION: In some definite cases, oral retinoids can be proposed as a treatment of cutaneous lesions in Bazex paraneoplastic acrokeratosis.

Influence des ions sur le pouvoir hydratant de l'ure e: e tude sur peau de porc ex vivo.

This study deals with the influence of ions (NaCl and MgSO4) in a W/O emulsion containing 10% urea. Moisturization kinetics are assessed by corneometry on pig skin ex vivo. The formula's influence on urea penetration is measured by infrared spectrometry with an ATR device and the stripping method. Corneometry and spectroscopy were chosen to record simultaneously the hydratation levels and urea localization into superficial cell layers. Urea crystallization after evaporation of emulsions and aqueous solutions is described. Results show that urea does not hydrate nor penetrate when applied to the skin through an aqueous gel. In a W/O emulsion, sodium chloride increases the ability of urea to moisturize without improving penetration. In vitro urea crystallization is disturbed by sodium chloride or magnesium sulphate for solutions and emulsions. This stabilization by ions is correlated with good moisturization values. The stabilization of urea in the solute state provided by ions increases its water epidermal binding capacity without enhancing penetration.

[Modulation of the organization of the extracellular matrix and the production of collagen by interferon gamma in three-dimensional cultures of normal and sclerodermic fibroblasts]. / Modulation de l'organisation de la matrice extracellulaire et de la production de collagène par l'interféron gamma dans des cultures tridimensionnelles de fibroblastes normaux et sclérodermiques.

Recent studies have shown inhibition of collagen synthesis by interferon gamma (IFN-gamma) in monolayer human fibroblast cultures on a plastic solid phase. However, the existence of this effect in vivo has not yet been demonstrated. Three-dimensional fibroblast cultures in collagen matrices (collagen lattices or dermal equivalents) provide a more physiological model than conventional cultures and fairly closely simulate in vivo conditions. This model was used for studying effects of IFN-gamma on normal and scleroderma fibroblasts. IFN-gamma induced a dose-dependent inhibition of fibroblast-mediated retraction of collagen lattices. IFN-gamma also inhibited total protein and collagen synthesis. Scleroderma fibroblasts were especially susceptible to the inhibitory effects of IFN-gamma. Since fibrotic scleroderma lesions are associated with tissue retraction and increased production of extracellular matrix macromolecules, these data confirm the potential value of IFN-gamma for the treatment of scleroderma and other fibrotic diseases.