Laurence Michel - Academia.edu (original) (raw)

Papers by Laurence Michel

Journal of the American Academy of Dermatology, 2015

Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involve... more Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. Retrospective design and small sample size are limitations. Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

La Revue de Médecine Interne, 2009

La meilleure connaissance des mécanismes pathogéniques de la fibrose tissulaire, notamment du rôl... more La meilleure connaissance des mécanismes pathogéniques de la fibrose tissulaire, notamment du rôle central des composants de la matrice extracellulaire (MEC), éclaire d'un jour nouveau l'utilisation d'immunosuppresseurs dans le traitement de la sclérodermie systémique (ScS). Nous présentons ici les travaux expérimentaux récents démontrant les propriétés antifibrosantes spécifiques de certains immunosuppresseurs, indépendamment de leur action immunosuppressive, en regard des résultats cliniques observés chez les patients traités pour ScS sévère. L'identification des mécanismes moléculaires à l'origine des effets de certains immunosuppresseurs (rapamycine et mycophénolate mofétil [MMF]) sur les fonctions fibroblastiques devraient permettre d'identifier des substances de choix dans le traitement de la ScS. © 2009 Société nationale française de médecine interne (SNFMI). Publié par Elsevier Masson SAS. Tous droits réservés.

La Revue de Médecine Interne, 2008

Objectif.-La mesure du score de Rodnan modifié (mRSS) a montré une régression de la fibrose cutan... more Objectif.-La mesure du score de Rodnan modifié (mRSS) a montré une régression de la fibrose cutanée chez les patients atteints de sclérodermie systémique sévère après autogreffe de cellules souches hématopoïétiques périphériques (ACSHP).

American Journal of Pathology, 2001

Recent data have suggested that in psoriasis, the Tinfiltrating cells could be submitted to regul... more Recent data have suggested that in psoriasis, the Tinfiltrating cells could be submitted to regulatory pathways, possibly through natural killer receptors. HLA-G binds to different natural killer receptors and is able to inhibit T-cell functions. Because this molecule is induced by interferon-␥, a major cytokine in psoriasis, we asked whether HLA-G and its receptor might be expressed in this disease. Specific RNAs for HLA-G1 and HLA-G5 were consistently found in lesional skin specimens, soluble HLA-G5 transcripts being found only in psoriasis. HLA-G protein was found in all psoriatic sections, but never in normal skin controls. Double labeling demonstrated that HLA-Gpositive cells were CD68 ؉ , CD11c ؉ macrophages. The NKR ILT2 was also present in psoriatic skin, the T CD4 ؉ -infiltrating cells expressing indeed ILT2. The demonstration of HLA-G and ILT2 expression in psoriatic skin suggests that this pathway may act as an inhibitory feed back aimed to down-regulate the deleterious effects of T-cell infiltrate in this disease.

PLoS ONE, 2014

Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to res... more Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to restore the barrier function of the skin. The calcineurin/nuclear factor of activated-T-cell (NFAT) signaling pathway has been recently shown to be involved in keratinocyte growth, differentiation and migration. It is induced by an increased intracellular calcium rate and its inhibition results in decreased capacities of keratinocytes to migrate. Nevertheless, the link between calcineurin activation and keratinocyte migration remains unknown. Recently, Orai1, a pore subunit of a store-operated calcium channel that favors calcium influx, was shown to play a critical role to control proliferation and migration of basal keratinocytes. Of interest, the actin-bundling T-plastin is crucial in cell motility through cross-linking to actin filament and its synthesis was shown to be induced by calcium influx and regulated by the calcineurin/NFAT pathway in tumor Sezary cells. We investigated herein the role of the calcineurin/NFAT pathway-dependent T-plastin in keratinocyte migration, by quantifying T-plastin expression in keratinocytes and by analyzing their migration under calcineurin inhibition or knockdown of NFAT2 or T-plastin. We did confirm the role of the calcineurin/NFAT pathway in keratinocyte migration as shown by their decreased capacities to migrate after FK506 treatment or siNFAT2 transfection in both scratching and Boyden assays. The expression of NFAT2 and T-plastin in keratinocytes was decreased under FK506 treatment, suggesting that T-plastin plays a role in keratinocyte migration downstream to the calcineurin/NFAT pathway. Accordingly, siRNA knockdown of T-plastin expression also decreased their migration capacities. Actin lamellipodia formation as well as FAK and b6-integrin expression were also significantly decreased after treatment with FK506 or siRNA, reinforcing that NFAT2-dependent T-plastin expression plays a role in keratinocyte migration. These results indicate that T-plastin might be considered as a major actor in the mechanisms underlying calcineurin/NFAT-dependent keratinocyte migration and may explain wound-healing defects observed in patients under calcineurin inhibitor long-term treatment.

Oncogene, 2002

The p16INK4A-ARF locus plays a crucial role in the control of cellular proliferation via both the... more The p16INK4A-ARF locus plays a crucial role in the control of cellular proliferation via both the Rb and P53 pathways. We previously demonstrated that this locus is altered in human skin carcinomas. In the present study we have studied the expression of the p16INK4A-ARF locus following UVB irradiation of normal human keratinocytes both at the mRNA (RT–PCR) and at the

Sezary syndrome is a leukemic form of epidermotropic cutaneous T-cell lym- phoma related to the m... more Sezary syndrome is a leukemic form of epidermotropic cutaneous T-cell lym- phoma related to the malignant prolifera- tion of clonal CD4 T cells. Extracorpo- real photochemotherapy may induce a transient improvement of the clinical signs, but its efficiency is discussed. To investigate the frequency of the T-cell clone in the peripheral blood of patients with Sezary syndrome and to monitor

Journal of Investigative Dermatology, 2014

The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS... more The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF), in particular, at early stages of the disease. We defined the CD158k/KIR3DL2 molecule as a first positive cell surface marker for Sézary cells (SCs). Here, we designed an optimized flow cytometry gating strategy, allowing the definition of lymphocytes of different sizes and defects of cell surface markers. Quantification by cytomorphology, flow cytometry, or clonal evaluation, gave similar results at initial time points and during the evolution in a prospective study involving 64 consecutive cutaneous T-cell lymphoma or erythrodermic patients. We found that CD158k+ T cells and circulating CD4+ T cells from MF patients exhibited unexpected patterns of cell surface expression with a marked heterogeneity of circulating lymphocytes even at initial diagnosis. Taken together, our results show that a multistep gating of CD158k+ cells is reliable to assess tumor burden in case of SS and suggest that both circulating MF CD4+ T cells and CD158k+ T cells are not homogeneous distinct memory populations. Further phenotypic and functional characterizations of such subsets are needed to better understand the underlying molecular mechanisms leading to the development of these diseases.

The EMBO Journal, 2009

The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after ca... more The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after caspase cleavage. However, this role has been challenged by recent observations suggesting a contribution of Acinus in apoptotic internucleosomal DNA cleavage. We report here that AAC-11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinusmediated DNA fragmentation. AAC-11 was able to protect Acinus from caspase-3 cleavage in vivo and in vitro, thus interfering with its biological function. Interestingly, AAC-11 depletion markedly increased cellular sensitivity to anticancer drugs, whereas its expression interfered with drug-induced cell death. AAC-11 possesses a leucine-zipper domain that dictates, upon oligomerization, its interaction with Acinus as well as the antiapoptotic effect of AAC-11 on drug-induced cell death. A cell permeable peptide that mimics the leucine-zipper subdomain of AAC-11, thus preventing its oligomerization, inhibited the AAC-11-Acinus complex formation and potentiated drug-mediated apoptosis in cancer cells. Our results, therefore, show that targeting AAC-11 might be a potent strategy for cancer treatment by sensitization of tumour cells to chemotherapeutic drugs.

Journal of Investigative Dermatology, 1992

Journal of Investigative Dermatology, 2004

Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to dr... more Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes

Journal of Investigative Dermatology, 2003

Arsenic trioxide (As 2 O 3 ) displays apoptogenic properties against various types of hematopoiet... more Arsenic trioxide (As 2 O 3 ) displays apoptogenic properties against various types of hematopoietic malignancies. We investigated the e¡ects of As 2 O 3 on the viability of the cutaneous T cell lymphoma cell lines HuT-78, SeAx, and Myla, and of peripheral blood mononuclear cells from patients with Se Ł zary syndrome, by using propidium iodide and annexin-V staining, terminal deoxyuridine triphosphate nick end labeling (TUNEL), cell cycle analysis, mitochondrial transmembrane potential (DW m ) alterations, cytochrome c release, and detection of processed caspase-3. We also report in vivo e¡ects of As 2 O 3 in two patients with cutaneous T cell lymphoma. The results show that As 2 O 3 induces apoptosis of cutaneous T cell lymphoma lines and of Se Ł zary cells from patients in a time-and concentration-dependent manner in vitro, as demonstrated by annexin-V staining, mitochondrial depolarization, and DNA fragmentation. Ascorbic acid 100 lM potentiated As 2 O 3 -induced Se Ł zary cell death, whereas interferon-a had no synergistic e¡ect. As 2 O 3 -induced Se Ł zary cell death involves activation of caspase-3, cleavage of poly(ADP-ribose)polymerase, and cytochrome c release, but was only partially inhibited by the pancaspase inhibitor Z-VAD.£uoromethylketone. Finally, As 2 O 3 was administered to two patients with cutaneous T cell lymphoma, allowing us to obtain a partial response in one case, whereas stability was observed in the second patient. These results demonstrate that As 2 O 3 synergizes with ascorbic acid to induce Se Ł zary cell death at clinically achievable concentrations, through a caspase-partially independent pathway, and provide a rationale for further in vivo studies addressing the therapeutic e⁄cacy of As 2 O 3 in cutaneous T cell lymphoma patients. Key words: arsenic trioxide/Se Ł zary syndrome/apoptosis/vitamin C/cutaneous T cell lymphoma.

Journal of Investigative Dermatology, 2004

We have previously observed that near-infrared (IR) pre-irradiation protects normal human dermal ... more We have previously observed that near-infrared (IR) pre-irradiation protects normal human dermal fibroblasts from ultraviolet (UV) cytotoxicity in vitro. Here, we show that IR pre-irradiation of human fibroblasts inhibited UVB activation of caspase-9 and -3, leading us to study early events in the mitochondrial apoptotic pathway after IR irradiation. IR irradiation led to a partial release of cytochrome c and Smac/Diablo but not apoptosis-inducing factor (AIF). This was accompanied by a slight but transient decrease in the mitochondrial membrane potential (Dw m ) and by the insertion of Bax into mitochondrial membrane. Early apoptotic events in the mitochondrial pathway thus occurred after IR irradiation despite a lack of caspase-9 and -3 activation. This could be explained by the induction by IR of the expression of heat shock protein Hsp27, which is known to prevent apoptosome assembly. Furthermore, the balance between pro-apoptotic (i.e., Bax) and anti-apoptotic (i.e., Bcl-2 or Bcl-x L ) proteins, which was rather pro-apoptotic after IR exposure, became anti-apoptotic 24 h later, suggesting a protective effect. Together, these actions could also contribute to prepare the cell to resist UVB-triggered apoptosis. Finally, isolated rat liver mitochondria-released cytochrome c in response to IR, demonstrating that mitochondria were a primary target of IR radiation.

Journal of Dermatological Science, 1998

A IN SEVERE ATOPIC DERMATITIS W Czech. Vdlmnen. E. Schaof. Umventtv of Fraburs; M Brautwm. G. Wel... more A IN SEVERE ATOPIC DERMATITIS W Czech. Vdlmnen. E. Schaof. Umventtv of Fraburs; M Brautwm. G. Welduuzcr, Nova& Phamm GmbH. Nbmherr. Germanv In tbls multicenter, double-blind study 106 patmtts wtb severe atopic dermautis were randomly allocated to a treatment wth dmly doses of e&r I.50 or 300 mg cyclospam A micrcemulsmn (Neoral) After two weeks of treatment the dose could he reduced by 50% m responders wrtb a reductmn of at Icast 50% m the Total-Body-Seventy-Assessment (TBSA) score

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1997

The human immature K562 erythroid cell line was studied for its capacity to produce and to metabo... more The human immature K562 erythroid cell line was studied for its capacity to produce and to metabolize the phospholipid Ž . molecule platelet-activating factor PAF . K562 cells produced PAF under calcium ionophore stimulation. Lyso PAF and Ž . acetyl-CoA the acetate donor molecule for the acetylation of lyso PAF into PAF had no effect on the amounts of PAF produced by ionophore-stimulated cells. The metabolism of PAF and lyso PAF by K562 cells was compared to that of w 3 x freshly-isolated human bone marrow erythroblasts and blood erythrocytes. K562 cells rapidly metabolized H PAF and w 3 x H lyso PAF with 1-alkyl analogue of phosphatidylcholine as the major metabolic product. In contrast, blood erythrocytes did not. PAF acetylhydrolase activity levels in K562 cells and bone marrow erythroblasts were similar and higher than in Ž .

International Journal of Cancer, 2004

Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T c... more Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T cells. In mice, we have demonstrated that, depending on the model, IL-17 may act as a tumor growth-promoting or -inhibiting factor. In order to address the relevance of these models in human tumors, we look for the natural expression and activity of IL-17 in mycosis fungoides (MF) and Sezary syndrome (SS). These cutaneous T-cell lymphomas were selected because they are usually CD3+ CD4+ CD45RO+, a phenotype similar to nontransformed T cells producing IL-17. We show that in vitro activated malignant T cells derived from MF or SS patients express IL-17 mRNA and secrete this cytokine. However, IL-17 does not act in vitro as a growth factor for MF or SS cell lines. In addition, 5 out of 10 MF/SS biopsies expressed IL-17 mRNA, while this cytokine was not detected in normal skin. IL-17 was not observed in the biopsies derived from 2 patients initially identified as MF, whereas an upregulation of this cytokine was clearly demonstrated during progression of the disease in these patients. An association between IL-17 expression and polymorphonuclear neutrophil infiltration was also recorded in this group of MF/SS patients. A more detailed analysis of 2 patients with a pustular form of MF and SS revealed that IL-17 may participate in the recruitment of polymorphonuclear neutrophils via a paracrine mechanism involving keratinocyte-released IL-8. This study is the first report demonstrating that some human tumor cells could express IL-17, a cytokine that represents an early event in the development of the inflammatory reaction within the tumor microenvironment, a process that may influence tumor phenotype and growth.

Journal of the American Academy of Dermatology, 2015

Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involve... more Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. Retrospective design and small sample size are limitations. Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

La Revue de Médecine Interne, 2009

La meilleure connaissance des mécanismes pathogéniques de la fibrose tissulaire, notamment du rôl... more La meilleure connaissance des mécanismes pathogéniques de la fibrose tissulaire, notamment du rôle central des composants de la matrice extracellulaire (MEC), éclaire d'un jour nouveau l'utilisation d'immunosuppresseurs dans le traitement de la sclérodermie systémique (ScS). Nous présentons ici les travaux expérimentaux récents démontrant les propriétés antifibrosantes spécifiques de certains immunosuppresseurs, indépendamment de leur action immunosuppressive, en regard des résultats cliniques observés chez les patients traités pour ScS sévère. L'identification des mécanismes moléculaires à l'origine des effets de certains immunosuppresseurs (rapamycine et mycophénolate mofétil [MMF]) sur les fonctions fibroblastiques devraient permettre d'identifier des substances de choix dans le traitement de la ScS. © 2009 Société nationale française de médecine interne (SNFMI). Publié par Elsevier Masson SAS. Tous droits réservés.

La Revue de Médecine Interne, 2008

Objectif.-La mesure du score de Rodnan modifié (mRSS) a montré une régression de la fibrose cutan... more Objectif.-La mesure du score de Rodnan modifié (mRSS) a montré une régression de la fibrose cutanée chez les patients atteints de sclérodermie systémique sévère après autogreffe de cellules souches hématopoïétiques périphériques (ACSHP).

American Journal of Pathology, 2001

Recent data have suggested that in psoriasis, the Tinfiltrating cells could be submitted to regul... more Recent data have suggested that in psoriasis, the Tinfiltrating cells could be submitted to regulatory pathways, possibly through natural killer receptors. HLA-G binds to different natural killer receptors and is able to inhibit T-cell functions. Because this molecule is induced by interferon-␥, a major cytokine in psoriasis, we asked whether HLA-G and its receptor might be expressed in this disease. Specific RNAs for HLA-G1 and HLA-G5 were consistently found in lesional skin specimens, soluble HLA-G5 transcripts being found only in psoriasis. HLA-G protein was found in all psoriatic sections, but never in normal skin controls. Double labeling demonstrated that HLA-Gpositive cells were CD68 ؉ , CD11c ؉ macrophages. The NKR ILT2 was also present in psoriatic skin, the T CD4 ؉ -infiltrating cells expressing indeed ILT2. The demonstration of HLA-G and ILT2 expression in psoriatic skin suggests that this pathway may act as an inhibitory feed back aimed to down-regulate the deleterious effects of T-cell infiltrate in this disease.

PLoS ONE, 2014

Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to res... more Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to restore the barrier function of the skin. The calcineurin/nuclear factor of activated-T-cell (NFAT) signaling pathway has been recently shown to be involved in keratinocyte growth, differentiation and migration. It is induced by an increased intracellular calcium rate and its inhibition results in decreased capacities of keratinocytes to migrate. Nevertheless, the link between calcineurin activation and keratinocyte migration remains unknown. Recently, Orai1, a pore subunit of a store-operated calcium channel that favors calcium influx, was shown to play a critical role to control proliferation and migration of basal keratinocytes. Of interest, the actin-bundling T-plastin is crucial in cell motility through cross-linking to actin filament and its synthesis was shown to be induced by calcium influx and regulated by the calcineurin/NFAT pathway in tumor Sezary cells. We investigated herein the role of the calcineurin/NFAT pathway-dependent T-plastin in keratinocyte migration, by quantifying T-plastin expression in keratinocytes and by analyzing their migration under calcineurin inhibition or knockdown of NFAT2 or T-plastin. We did confirm the role of the calcineurin/NFAT pathway in keratinocyte migration as shown by their decreased capacities to migrate after FK506 treatment or siNFAT2 transfection in both scratching and Boyden assays. The expression of NFAT2 and T-plastin in keratinocytes was decreased under FK506 treatment, suggesting that T-plastin plays a role in keratinocyte migration downstream to the calcineurin/NFAT pathway. Accordingly, siRNA knockdown of T-plastin expression also decreased their migration capacities. Actin lamellipodia formation as well as FAK and b6-integrin expression were also significantly decreased after treatment with FK506 or siRNA, reinforcing that NFAT2-dependent T-plastin expression plays a role in keratinocyte migration. These results indicate that T-plastin might be considered as a major actor in the mechanisms underlying calcineurin/NFAT-dependent keratinocyte migration and may explain wound-healing defects observed in patients under calcineurin inhibitor long-term treatment.

Oncogene, 2002

The p16INK4A-ARF locus plays a crucial role in the control of cellular proliferation via both the... more The p16INK4A-ARF locus plays a crucial role in the control of cellular proliferation via both the Rb and P53 pathways. We previously demonstrated that this locus is altered in human skin carcinomas. In the present study we have studied the expression of the p16INK4A-ARF locus following UVB irradiation of normal human keratinocytes both at the mRNA (RT–PCR) and at the

Sezary syndrome is a leukemic form of epidermotropic cutaneous T-cell lym- phoma related to the m... more Sezary syndrome is a leukemic form of epidermotropic cutaneous T-cell lym- phoma related to the malignant prolifera- tion of clonal CD4 T cells. Extracorpo- real photochemotherapy may induce a transient improvement of the clinical signs, but its efficiency is discussed. To investigate the frequency of the T-cell clone in the peripheral blood of patients with Sezary syndrome and to monitor

Journal of Investigative Dermatology, 2014

The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS... more The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF), in particular, at early stages of the disease. We defined the CD158k/KIR3DL2 molecule as a first positive cell surface marker for Sézary cells (SCs). Here, we designed an optimized flow cytometry gating strategy, allowing the definition of lymphocytes of different sizes and defects of cell surface markers. Quantification by cytomorphology, flow cytometry, or clonal evaluation, gave similar results at initial time points and during the evolution in a prospective study involving 64 consecutive cutaneous T-cell lymphoma or erythrodermic patients. We found that CD158k+ T cells and circulating CD4+ T cells from MF patients exhibited unexpected patterns of cell surface expression with a marked heterogeneity of circulating lymphocytes even at initial diagnosis. Taken together, our results show that a multistep gating of CD158k+ cells is reliable to assess tumor burden in case of SS and suggest that both circulating MF CD4+ T cells and CD158k+ T cells are not homogeneous distinct memory populations. Further phenotypic and functional characterizations of such subsets are needed to better understand the underlying molecular mechanisms leading to the development of these diseases.

The EMBO Journal, 2009

The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after ca... more The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after caspase cleavage. However, this role has been challenged by recent observations suggesting a contribution of Acinus in apoptotic internucleosomal DNA cleavage. We report here that AAC-11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinusmediated DNA fragmentation. AAC-11 was able to protect Acinus from caspase-3 cleavage in vivo and in vitro, thus interfering with its biological function. Interestingly, AAC-11 depletion markedly increased cellular sensitivity to anticancer drugs, whereas its expression interfered with drug-induced cell death. AAC-11 possesses a leucine-zipper domain that dictates, upon oligomerization, its interaction with Acinus as well as the antiapoptotic effect of AAC-11 on drug-induced cell death. A cell permeable peptide that mimics the leucine-zipper subdomain of AAC-11, thus preventing its oligomerization, inhibited the AAC-11-Acinus complex formation and potentiated drug-mediated apoptosis in cancer cells. Our results, therefore, show that targeting AAC-11 might be a potent strategy for cancer treatment by sensitization of tumour cells to chemotherapeutic drugs.

Journal of Investigative Dermatology, 1992

Journal of Investigative Dermatology, 2004

Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to dr... more Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes

Journal of Investigative Dermatology, 2003

Arsenic trioxide (As 2 O 3 ) displays apoptogenic properties against various types of hematopoiet... more Arsenic trioxide (As 2 O 3 ) displays apoptogenic properties against various types of hematopoietic malignancies. We investigated the e¡ects of As 2 O 3 on the viability of the cutaneous T cell lymphoma cell lines HuT-78, SeAx, and Myla, and of peripheral blood mononuclear cells from patients with Se Ł zary syndrome, by using propidium iodide and annexin-V staining, terminal deoxyuridine triphosphate nick end labeling (TUNEL), cell cycle analysis, mitochondrial transmembrane potential (DW m ) alterations, cytochrome c release, and detection of processed caspase-3. We also report in vivo e¡ects of As 2 O 3 in two patients with cutaneous T cell lymphoma. The results show that As 2 O 3 induces apoptosis of cutaneous T cell lymphoma lines and of Se Ł zary cells from patients in a time-and concentration-dependent manner in vitro, as demonstrated by annexin-V staining, mitochondrial depolarization, and DNA fragmentation. Ascorbic acid 100 lM potentiated As 2 O 3 -induced Se Ł zary cell death, whereas interferon-a had no synergistic e¡ect. As 2 O 3 -induced Se Ł zary cell death involves activation of caspase-3, cleavage of poly(ADP-ribose)polymerase, and cytochrome c release, but was only partially inhibited by the pancaspase inhibitor Z-VAD.£uoromethylketone. Finally, As 2 O 3 was administered to two patients with cutaneous T cell lymphoma, allowing us to obtain a partial response in one case, whereas stability was observed in the second patient. These results demonstrate that As 2 O 3 synergizes with ascorbic acid to induce Se Ł zary cell death at clinically achievable concentrations, through a caspase-partially independent pathway, and provide a rationale for further in vivo studies addressing the therapeutic e⁄cacy of As 2 O 3 in cutaneous T cell lymphoma patients. Key words: arsenic trioxide/Se Ł zary syndrome/apoptosis/vitamin C/cutaneous T cell lymphoma.

Journal of Investigative Dermatology, 2004

We have previously observed that near-infrared (IR) pre-irradiation protects normal human dermal ... more We have previously observed that near-infrared (IR) pre-irradiation protects normal human dermal fibroblasts from ultraviolet (UV) cytotoxicity in vitro. Here, we show that IR pre-irradiation of human fibroblasts inhibited UVB activation of caspase-9 and -3, leading us to study early events in the mitochondrial apoptotic pathway after IR irradiation. IR irradiation led to a partial release of cytochrome c and Smac/Diablo but not apoptosis-inducing factor (AIF). This was accompanied by a slight but transient decrease in the mitochondrial membrane potential (Dw m ) and by the insertion of Bax into mitochondrial membrane. Early apoptotic events in the mitochondrial pathway thus occurred after IR irradiation despite a lack of caspase-9 and -3 activation. This could be explained by the induction by IR of the expression of heat shock protein Hsp27, which is known to prevent apoptosome assembly. Furthermore, the balance between pro-apoptotic (i.e., Bax) and anti-apoptotic (i.e., Bcl-2 or Bcl-x L ) proteins, which was rather pro-apoptotic after IR exposure, became anti-apoptotic 24 h later, suggesting a protective effect. Together, these actions could also contribute to prepare the cell to resist UVB-triggered apoptosis. Finally, isolated rat liver mitochondria-released cytochrome c in response to IR, demonstrating that mitochondria were a primary target of IR radiation.

Journal of Dermatological Science, 1998

A IN SEVERE ATOPIC DERMATITIS W Czech. Vdlmnen. E. Schaof. Umventtv of Fraburs; M Brautwm. G. Wel... more A IN SEVERE ATOPIC DERMATITIS W Czech. Vdlmnen. E. Schaof. Umventtv of Fraburs; M Brautwm. G. Welduuzcr, Nova& Phamm GmbH. Nbmherr. Germanv In tbls multicenter, double-blind study 106 patmtts wtb severe atopic dermautis were randomly allocated to a treatment wth dmly doses of e&r I.50 or 300 mg cyclospam A micrcemulsmn (Neoral) After two weeks of treatment the dose could he reduced by 50% m responders wrtb a reductmn of at Icast 50% m the Total-Body-Seventy-Assessment (TBSA) score

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1997

The human immature K562 erythroid cell line was studied for its capacity to produce and to metabo... more The human immature K562 erythroid cell line was studied for its capacity to produce and to metabolize the phospholipid Ž . molecule platelet-activating factor PAF . K562 cells produced PAF under calcium ionophore stimulation. Lyso PAF and Ž . acetyl-CoA the acetate donor molecule for the acetylation of lyso PAF into PAF had no effect on the amounts of PAF produced by ionophore-stimulated cells. The metabolism of PAF and lyso PAF by K562 cells was compared to that of w 3 x freshly-isolated human bone marrow erythroblasts and blood erythrocytes. K562 cells rapidly metabolized H PAF and w 3 x H lyso PAF with 1-alkyl analogue of phosphatidylcholine as the major metabolic product. In contrast, blood erythrocytes did not. PAF acetylhydrolase activity levels in K562 cells and bone marrow erythroblasts were similar and higher than in Ž .

International Journal of Cancer, 2004

Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T c... more Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T cells. In mice, we have demonstrated that, depending on the model, IL-17 may act as a tumor growth-promoting or -inhibiting factor. In order to address the relevance of these models in human tumors, we look for the natural expression and activity of IL-17 in mycosis fungoides (MF) and Sezary syndrome (SS). These cutaneous T-cell lymphomas were selected because they are usually CD3+ CD4+ CD45RO+, a phenotype similar to nontransformed T cells producing IL-17. We show that in vitro activated malignant T cells derived from MF or SS patients express IL-17 mRNA and secrete this cytokine. However, IL-17 does not act in vitro as a growth factor for MF or SS cell lines. In addition, 5 out of 10 MF/SS biopsies expressed IL-17 mRNA, while this cytokine was not detected in normal skin. IL-17 was not observed in the biopsies derived from 2 patients initially identified as MF, whereas an upregulation of this cytokine was clearly demonstrated during progression of the disease in these patients. An association between IL-17 expression and polymorphonuclear neutrophil infiltration was also recorded in this group of MF/SS patients. A more detailed analysis of 2 patients with a pustular form of MF and SS revealed that IL-17 may participate in the recruitment of polymorphonuclear neutrophils via a paracrine mechanism involving keratinocyte-released IL-8. This study is the first report demonstrating that some human tumor cells could express IL-17, a cytokine that represents an early event in the development of the inflammatory reaction within the tumor microenvironment, a process that may influence tumor phenotype and growth.