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1.
Cell ; 151(2): 289-303, 2012 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-23021777

RESUMO

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.


Assuntos
Redes Reguladoras de Genes , Células Th17/citologia , Células Th17/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Diferenciação Celular , Encefalomielite Autoimune Experimental/imunologia , Antígeno 2 Relacionado a Fos/imunologia , Antígeno 2 Relacionado a Fos/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th17/imunologia
2.
Proc Natl Acad Sci U S A ; 121(18): e2404188121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38657045

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.


Assuntos
Carcinoma Hepatocelular , Antígeno 2 Relacionado a Fos , Neoplasias Hepáticas , Proteínas Proto-Oncogênicas c-fos , Proteínas Proto-Oncogênicas c-jun , Proteínas Proto-Oncogênicas c-myc , Fator de Transcrição AP-1 , Animais , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Antígeno 2 Relacionado a Fos/metabolismo , Antígeno 2 Relacionado a Fos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Hepatócitos/metabolismo , Multimerização Proteica , Regulação Neoplásica da Expressão Gênica , Camundongos Transgênicos
3.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35210363

RESUMO

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, ß-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine ß-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.


Assuntos
Tecido Adiposo Marrom/patologia , Caquexia/patologia , Comunicação Celular , Neoplasias/complicações , Neurônios/patologia , Sistema Nervoso Simpático/patologia , Animais , Caquexia/etiologia , Caquexia/metabolismo , Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Neoplasias/metabolismo , Receptores Adrenérgicos beta/metabolismo , Termogênese
4.
J Immunol ; 208(4): 941-954, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35082159

RESUMO

TPL-2 kinase plays an important role in innate immunity, activating ERK1/2 MAPKs in myeloid cells following TLR stimulation. We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos -/- macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.


Assuntos
Interferon beta/genética , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Regulação da Expressão Gênica , Interferon beta/metabolismo , Lipopolissacarídeos/imunologia , MAP Quinase Quinase Quinases/genética , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Transcrição TCF/metabolismo
5.
Nature ; 554(7693): 533-537, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29443959

RESUMO

Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2+/- mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2+/-mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica , Inflamação/genética , Pâncreas/metabolismo , Pâncreas/patologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transcriptoma , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Cromatina/genética , Cromatina/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Redes Reguladoras de Genes/genética , Genes jun/genética , Heterozigoto , Humanos , Camundongos , Especificidade de Órgãos/genética , Pancreatite/genética , Regiões Promotoras Genéticas/genética , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Fator de Transcrição AP-1/metabolismo
6.
Genes Dev ; 30(5): 489-501, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26944676

RESUMO

Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.


Assuntos
Caquexia/etiologia , Caquexia/fisiopatologia , Neoplasias/complicações , Tecido Adiposo Branco/fisiopatologia , Metabolismo dos Carboidratos/fisiologia , Sistema Endócrino/fisiopatologia , Humanos , Inflamação/complicações , Metabolismo dos Lipídeos , Fígado/fisiopatologia , Atrofia Muscular/etiologia
7.
Ann Rheum Dis ; 82(9): 1227-1239, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37344157

RESUMO

OBJECTIVES: The activator protein-1 (AP-1) transcription factor component c-Fos regulates chondrocyte proliferation and differentiation, but its involvement in osteoarthritis (OA) has not been functionally assessed. METHODS: c-Fos expression was evaluated by immunohistochemistry on articular cartilage sections from patients with OA and mice subjected to the destabilisation of the medial meniscus (DMM) model of OA. Cartilage-specific c-Fos knockout (c-FosΔCh) mice were generated by crossing c-fosfl/fl to Col2a1-CreERT mice. Articular cartilage was evaluated by histology, immunohistochemistry, RNA sequencing (RNA-seq), quantitative reverse transcription PCR (qRT-PCR) and in situ metabolic enzyme assays. The effect of dichloroacetic acid (DCA), an inhibitor of pyruvate dehydrogenase kinase (Pdk), was assessed in c-FosΔCh mice subjected to DMM. RESULTS: FOS-positive chondrocytes were increased in human and murine OA cartilage during disease progression. Compared with c-FosWT mice, c-FosΔCh mice exhibited exacerbated DMM-induced cartilage destruction. Chondrocytes lacking c-Fos proliferate less, have shorter collagen fibres and reduced cartilage matrix. Comparative RNA-seq revealed a prominent anaerobic glycolysis gene expression signature. Consistently decreased pyruvate dehydrogenase (Pdh) and elevated lactate dehydrogenase (Ldh) enzymatic activities were measured in situ, which are likely due to higher expression of hypoxia-inducible factor-1α, Ldha, and Pdk1 in chondrocytes. In vivo treatment of c-FosΔCh mice with DCA restored Pdh/Ldh activity, chondrocyte proliferation, collagen biosynthesis and decreased cartilage damage after DMM, thereby reverting the deleterious effects of c-Fos inactivation. CONCLUSIONS: c-Fos modulates cellular bioenergetics in chondrocytes by balancing pyruvate flux between anaerobic glycolysis and the tricarboxylic acid cycle in response to OA signals. We identify a novel metabolic adaptation of chondrocytes controlled by c-Fos-containing AP-1 dimers that could be therapeutically relevant.


Assuntos
Cartilagem Articular , Osteoartrite , Proteínas Proto-Oncogênicas c-fos , Animais , Humanos , Camundongos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Osteoartrite/patologia , Fator de Transcrição AP-1/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética
8.
Genes Dev ; 29(2): 144-56, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25547114

RESUMO

Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.


Assuntos
Diferenciação Celular , Antígeno 2 Relacionado a Fos/metabolismo , Queratinócitos/citologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos , Proteína Potenciadora do Homólogo 2 de Zeste , Regulação da Expressão Gênica no Desenvolvimento , Lisina/metabolismo , Metilação , Camundongos , Fosforilação
9.
Ann Rheum Dis ; 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35788494

RESUMO

OBJECTIVES: S100A9, an alarmin that can form calprotectin (CP) heterodimers with S100A8, is mainly produced by keratinocytes and innate immune cells. The contribution of keratinocyte-derived S100A9 to psoriasis (Ps) and psoriatic arthritis (PsA) was evaluated using mouse models, and the potential usefulness of S100A9 as a Ps/PsA biomarker was assessed in patient samples. METHODS: Conditional S100A9 mice were crossed with DKO* mice, an established psoriasis-like mouse model based on inducible epidermal deletion of c-Jun and JunB to achieve additional epidermal deletion of S100A9 (TKO* mice). Psoriatic skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA and proteomic analyses. Furthermore, S100A9 expression was analysed in skin, serum and synovial fluid samples of patients with Ps and PsA. RESULTS: Compared with DKO* littermates, TKO* mice displayed enhanced skin disease severity, PsA incidence and neutrophil infiltration. Altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3 and higher circulating TNFα were observed in TKO* mice. In humans, synovial S100A9 levels were higher than the respective serum levels. Importantly, patients with PsA had significantly higher serum concentrations of S100A9, CP, VEGF, IL-6 and TNFα compared with patients with only Ps, but only S100A9 and CP could efficiently discriminate healthy individuals, patients with Ps and patients with PsA. CONCLUSIONS: Keratinocyte-derived S100A9 plays a regulatory role in psoriatic skin and joint disease. In humans, S100A9/CP is a promising marker that could help in identifying patients with Ps at risk of developing PsA.

10.
Immunity ; 39(6): 1171-81, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24332034

RESUMO

Psoriasis is a common heterogeneous inflammatory skin disease with a complex pathophysiology and limited treatment options. Here we performed proteomic analyses of human psoriatic epidermis and found S100A8-S100A9, also called calprotectin, as the most upregulated proteins, followed by the complement component C3. Both S100A8-S100A9 and C3 are specifically expressed in lesional psoriatic skin. S100A9 is shown here to function as a chromatin component modulating C3 expression in mouse and human cells by binding to a region upstream of the C3 start site. When S100A9 was genetically deleted in mouse models of skin inflammation, the psoriasis-like skin disease and inflammation were strongly attenuated, with a mild immune infiltrate and decreased amounts of C3. In addition, inhibition of C3 in the mouse model strongly reduced the inflammatory skin disease. Thus, S100A8-S100A9 can regulate C3 at the nuclear level and present potential new therapeutic targets for psoriasis.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Complemento C3/genética , Regulação da Expressão Gênica , Psoríase/genética , Psoríase/fisiopatologia , Animais , Calgranulina A/genética , Calgranulina B/genética , Núcleo Celular/metabolismo , Células Cultivadas , Complemento C3/metabolismo , Modelos Animais de Doenças , Células Epidérmicas , Epiderme/imunologia , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteoma , Psoríase/imunologia , RNA Interferente Pequeno/metabolismo
11.
J Allergy Clin Immunol ; 147(6): 2386-2393.e4, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675820

RESUMO

BACKGROUND: The molecular control of inflammation and epidermal thickening in skin lesions of patients with atopic dermatitis (AD) is not known. Sequestosome 1/p62 is a multifunctional adapter protein implicated in the control of key regulators of cellular homeostasis, such as proinflammatory and mechanistic target of rapamycin signaling. OBJECTIVE: We sought to determine whether p62 plays a role in the cutaneous and systemic manifestations of an AD-like mouse model. METHODS: AD-like skin lesions were induced by deletion of JunB/AP-1, specifically in epidermal keratinocytes (JunBΔep). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunBΔepp62-/- double knockout mice. RESULTS: Expression of p62 was elevated in skin lesions of JunBΔep mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunBΔep-associated defects in the differentiation of keratinocytes, epidermal thickening, skin infiltration by mast cells and neutrophils, and the development of macroscopic skin lesions were significantly reduced. p62 inactivation had little effect on circulating cytokines, but decreased serum IgE. Signaling through mechanistic target of rapamycin and natural factor kappa B was increased in JunBΔep but not in JunBΔepp62-/- double knockout skin, indicating an important role of p62 in enhancing these signaling pathways in the skin during AD-like inflammation. CONCLUSIONS: Our results provide the first in vivo evidence for a proinflammatory role of p62 in skin and suggest that p62-dependent signaling pathways may be promising therapeutic targets to ameliorate the skin manifestations of AD and possibly psoriasis.


Assuntos
Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Suscetibilidade a Doenças , Proteína Sequestossoma-1/metabolismo , Animais , Biomarcadores , Doença Crônica , Dermatite Atópica/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Fenótipo , Proteína Sequestossoma-1/genética , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/patologia
12.
Gut ; 70(10): 1978-1988, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34145045

RESUMO

The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn's disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.


Assuntos
Biomarcadores/metabolismo , Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Algoritmos , Humanos , Valor Preditivo dos Testes , Sensibilidade e Especificidade
13.
Exp Dermatol ; 30(11): 1662-1674, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33998705

RESUMO

Psoriasis is a chronic inflammatory skin disease without cure. Systemic and biological therapies are the most effective treatments for patients with severe psoriasis. However, these drugs can cause serious side effects from extended use. Safe and effective topical drugs are needed to decrease psoriatic plaques and reduce the risk of adverse effects. Amygdalin analogues are stable small molecules that showed benefits in psoriasis xenografts to immune-deficient mice by systemic application. However, whether topical application of these amygdalin analogues could reduce the progression of the psoriatic phenotype in an immune-competent organism is unknown. Here, we analyse the efficiency of topical application of an amygdalin analogue cream on a well-established genetic and immune-competent mouse model of psoriasis. Topical application of an amygdalin analogue cream ameliorates psoriasis-like disease in mice, reduces epidermal hyperplasia and skin inflammation. Amygdalin analogue treatment leads to reduced expression of local pro-inflammatory cytokines, but systemic pro-inflammatory cytokines that are highly expressed in psoriasis patients such as IL-17A, IL6 or G-CSF are also decreased. Furthermore, expression of important mediators of psoriasis initiation and epidermal hyperplasia, such as TNFa, S100A9 and TSLP, is decreased in lesional epidermis after amygdalin analogue treatment. In conclusion, we show that amygdalin analogue reduces the proliferative capacity of psoriasis-like stimulated keratinocytes and their inflammatory response in vivo and in vitro. These results suggest that topical application of amygdalin analogues may represent a safe and effective treatment for psoriasis.


Assuntos
Amigdalina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Psoríase/tratamento farmacológico , Psoríase/patologia , Administração Tópica , Animais , Modelos Animais de Doenças , Formas de Dosagem , Camundongos
14.
Genes Dev ; 27(18): 1959-73, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-24029918

RESUMO

Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T-cell infiltration. Our studies demonstrate a bidirectional cross-talk between premalignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represents promising therapeutic strategies to treat SCCs.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Epiderme/metabolismo , Inflamação , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neoplasias Cutâneas/fisiopatologia , Animais , Benzo(a)Antracenos , Linfócitos T CD4-Positivos/citologia , Carcinoma de Células Escamosas/fisiopatologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/fisiopatologia , Masculino , Metaloproteinase 10 da Matriz/genética , Metaloproteinase 10 da Matriz/metabolismo , Camundongos , Papiloma/induzido quimicamente , Papiloma/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Transdução de Sinais
15.
Development ; 142(22): 3912-20, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26428006

RESUMO

Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through 'osteogenic capillaries' in a Fosl1-regulated manner.


Assuntos
Capilares/fisiologia , Cartilagem/embriologia , Martelo/embriologia , Osteogênese/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Matriz Óssea/metabolismo , Capilares/metabolismo , Cartilagem/irrigação sanguínea , Técnicas Histológicas , Processamento de Imagem Assistida por Computador , Martelo/irrigação sanguínea , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Osteoblastos/metabolismo , Síncrotrons , Tomografia Computadorizada por Raios X
16.
EMBO J ; 32(16): 2248-63, 2013 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-23860128

RESUMO

Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA-34a (miR-34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR-34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild-type p53 expression. In normal HKCs, the pro-differentiation effects of increased p53 activity or UVB exposure are miR-34a-dependent, and increased miR-34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR-34a function, is a direct target of this miRNA in HKCs, and SIRT6 down-modulation is sufficient to reproduce the miR-34a pro-differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR-34a in normal keratinocytes and keratinocyte-derived tumours.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Queratinócitos/fisiologia , MicroRNAs/metabolismo , Sirtuínas/metabolismo , Diferenciação Celular/efeitos da radiação , Primers do DNA/genética , Humanos , Queratinócitos/metabolismo , Análise em Microsséries , Reação em Cadeia da Polimerase em Tempo Real , Receptor Notch1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta
18.
Proc Natl Acad Sci U S A ; 111(49): 17582-7, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25422452

RESUMO

The inflamed tumor microenvironment plays a critical role in tumorigenesis. However, the mechanisms through which immune cells, particularly macrophages, promote tumorigenesis have only been partially elucidated, and the full scope of signaling pathways supplying macrophages with protumorigenic phenotypes still remain largely unknown. Here we report that germ-line absence of c-Jun N-terminal phosphorylation at serines 63 and 73 impedes inflammation-associated hepatocarcinogenesis, yet deleting c-Jun only in hepatocytes does not inhibit hepatocellular carcinoma (HCC) formation. Moreover, in human HCC-bearing livers, c-Jun phosphorylation is found in inflammatory cells, whereas it is mostly absent from malignant hepatocytes. Interestingly, macrophages in livers of mice with chronic hepatitis gradually switch their phenotype along the course of disease. Macrophage phenotype and density are dictated by c-Jun phosphorylation, in vitro and in vivo. Transition of macrophage phenotype, from antitumorigenic to protumorigenic, occurs before tumorigenesis, resulting in the production of various chemokines, including chemokine (C-C motif) ligand 17 (CCL17) and CCL22. Such signals, emanating from the liver microenvironment, direct the recruitment of regulatory T cells, which are known to facilitate HCC growth. Our findings identify c-Jun phosphorylation as a key mediator of macrophage education and point to the recruitment of immunosuppressive regulatory T cells as a possible protumorigenic mechanism.


Assuntos
Macrófagos/citologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Quimiocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Hepatite/metabolismo , Hepatócitos/citologia , Humanos , Imunidade Inata , Inflamação , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Fosforilação , Prognóstico , Estrutura Terciária de Proteína , Microambiente Tumoral
19.
Genes Dev ; 23(22): 2663-74, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19933155

RESUMO

Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNFalpha play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNFalpha shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNFalpha-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNFalpha shedding upon loss of both JunB and c-Jun. Consequently, a prominent TNFalpha-dependent cytokine cascade is initiated in the epidermis, inducing severe skin inflammation and perinatal death of newborns from exhaustion of energy reservoirs such as glycogen and lipids. Importantly, this metabolic "cachectic" phenotype can be genetically rescued in a TNFR1-deficient background or by epidermis-specific re-expression of TIMP-3. These findings reveal that Jun proteins are essential physiological regulators of TNFalpha shedding by controlling the TIMP-3/TACE pathway. This novel mechanism describing how Jun proteins control skin inflammation offers potential targets for the treatment of skin pathologies associated with increased TNFalpha levels.


Assuntos
Epiderme/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Caquexia/genética , Caquexia/mortalidade , Células Cultivadas , Citocinas/metabolismo , Epiderme/patologia , Regulação da Expressão Gênica , Inflamação/fisiopatologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-jun/deficiência , Proteínas Proto-Oncogênicas c-jun/genética , Dermatopatias/fisiopatologia , Inibidor Tecidual de Metaloproteinase-3/metabolismo
20.
Clin Exp Rheumatol ; 34(4 Suppl 98): 17-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27586798

RESUMO

Inflammation is a physiological reaction to tissue injury, pathogen invasion and a natural response to various stress stimuli. Innate and adaptive immune cells are activated and recruited to the site of inflammation to suppress or promote inflammation. The recruitment and activation of immune cells is modulated by cytokines and chemokines, which are regulated by transcription factors, such as AP-1 (Fos/Jun), NF-kB, NFATs and STATs. Moreover, it is now appreciated that chronic inflammation can lead to systemic effects affecting the whole organism by mechanisms which are not well understood.Here we review our recent data obtained from the analyses of psoriasis patient samples as well as from AP-1 (Fos/Jun)-dependent, genetically engineered mouse models. The deletion of two AP-1 factors JunB and c-Jun in an inducible manner in adult mice, specifically in Keratin-5 expressing tissues, leads to a psoriasis-like disease. Importantly, the epidermal proteome of the mutant mice is comparable to psoriasis patient samples. Our analyses revealed that the activation of S100A8/A9-dependent C3 complement as well as a miR-21-dependent TIMP-3/TACE pathway leading to TNF-α shedding, are causally involved in disease development.Epidermal deletion of only JunB in mice leads to chronic skin inflammation with increased levels of pro-inflammatory cytokines and multi-organ involvement. Our recent findings show that chronic skin inflammation induces bone loss through systemic elevated IL-17A signalling. This novel mechanism involves inhibition of osteoblast-mediated bone formation by reduced Wnt signalling with no effect on RANKL-dependent osteoclastic bone resorption. These data have important translational implications; blocking of IL-17A signalling, which is already approved for the treatment of psoriasis, should also be considered to prevent the adverse skeletal consequences of chronic inflammatory diseases.


Assuntos
Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-17/metabolismo , Psoríase/metabolismo , Pele/metabolismo , Via de Sinalização Wnt , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/imunologia , Reabsorção Óssea/patologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/imunologia , Interleucina-17/imunologia , Camundongos Transgênicos , Fenótipo , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia
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