RESUMO
INTRODUCTION: We evaluated sequelae of disease and therapy in adolescents with chronic endocrinopathies using a medical and psychological workup to record health-related quality of life (HRQoL), near final height (NFH) and body compositions during the transition period from paediatric to adult care. METHODS: Near final height, weight, body mass index (BMI), grip strength (GS), hip and waist circumference (HC; WC), skin folds (SF) and HRQoL T-scores by KIDSCREEN and DISABKIDS were assessed in 134 patients (70 females and 64 males) from May 2010 to March 2016 diagnosed with congenital adrenal hyperplasia (CAH; n = 22), multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 37), Turner syndrome (TS; n = 27), SGA-short stature (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). RESULTS: Median HRQoL T-scores for KIDSCREEN (50.6-56.5) and DISABKIDS (52.7-58.9) ranged within references with considerable variations but without significant deficit in any diagnosis. Median-corrected height SDS (CoH-SDS: NFH-SDS-TH [target height]-SDS) was >-1, except in KS (SDS + 1.3) and in TS (SDS - 1.9; P < .0001) without correlations with HRQoL. Median BMI was below 25 kg/m2 in all patients except MPHD (26.5 kg/m2 ; SDS 1.5; P = .006). BMI correlated negatively in CAH females with self-perception (rs = -.64, P = .0338), physical well-being (rs = -.8; P = .0086), social exclusion rs = -.65; P = .031) and emotions (rs = -.7; P = .0169). CONCLUSION: Health-related quality of life and body compositions were similar to those of healthy adolescents. Lower scores in HRQoL dimensions as self-perception, physical well-being, social exclusion and emotions were detected and correlated negatively with BMI. Treatment strategies and psychological support should consider HRQoL and adapted in specific treatment guidelines.
Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Transição para Assistência do Adulto , Adolescente , Adulto , Composição Corporal , Estatura , Criança , Feminino , Humanos , Masculino , Qualidade de VidaRESUMO
NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.
Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Minociclina/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antibacterianos/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Minociclina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagemAssuntos
Antibacterianos/uso terapêutico , Encéfalo/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Tetraciclinas/uso terapêutico , Fatores Etários , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Citoproteção , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Fatores de RiscoRESUMO
Diverse nuclear factor-kappaB subunits mediate opposite effects of extracellular signals on neuron survival. While RelA is activated by neurotoxic agents, c-Rel drives neuroprotective effects. In brain ischaemia RelA and p50 factors rapidly activate, but how they associate with c-Rel to form active dimers and contribute to the changes in diverse dimer activation for neuron susceptibility is unknown. We show that in both cortical neurons exposed to oxygen glucose deprivation (OGD) and mice subjected to brain ischaemia, activation of p50/RelA was associated with inhibition of c-Rel/RelA dimer and no change p50/c-Rel. Targeting c-Rel and RelA expression revealed that c-Rel dimers reduced while p50/RelA enhanced neuronal susceptibility to anoxia. Activation of p50/RelA complex is known to induce the pro-apoptotic Bim and Noxa genes. We now show that c-Rel-containing dimers, p50/c-Rel and RelA/c-Rel, but not p50/RelA, promoted Bcl-xL transcription. Accordingly, the OGD exposure induced Bim, but reduced Bcl-xL promoter activity and decreased the content of endogenous Bcl-xL protein. These findings demonstrate that within the same neuronal cell, the balance between activation of p50/RelA and c-Rel-containing complexes fine tunes the threshold of neuron vulnerability to the ischaemic insult. Selective targeting of different dimers will unravel new approaches to limit ischaemia-associated apoptosis.
Assuntos
Infarto da Artéria Cerebral Média/patologia , Subunidade p50 de NF-kappa B/metabolismo , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-rel/fisiologia , Fator de Transcrição RelA/fisiologia , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Regulação da Expressão Gênica/fisiologia , Glucose/deficiência , Humanos , Hipóxia , Imunoprecipitação/métodos , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/genética , Neuroblastoma , Proteínas Proto-Oncogênicas c-rel/genética , RNA Interferente Pequeno/farmacologia , Fator de Transcrição RelA/genética , Transfecção/métodos , Proteína bcl-X/metabolismoRESUMO
Background 11ß-hydroxylase deficiency (11ßOHD) is a rare disease representing the second most common cause of congenital adrenal hyperplasia (CAH) (5-8%) with an incidence of about 1:100,000. In contrast to 21-hydroxylase deficiency (21OHD), 11ßOHD is not included in neonatal screening programmes. The objective of this study was to demonstrate the typical features of male patients with 11ßOHD. Methods Clinical, biochemical and radiological data of patients with 11ßOHD were analysed in this retrospective single-centre analysis. Results Six male patients of four unrelated families with 11ßOHD were identified (0.1-13.5 years of chronological age [CA] at diagnosis). The predominant symptoms were arterial hypertension, tall stature and precocious pseudopuberty. Bone ages (BAs) were remarkably advanced at diagnosis in four index patients (median difference BA-CA: 5.5 years, range 1.5-9.2 years). Homozygous mutations were identified in exon 7 (c.1179_1180dupGA [p.Asn394Argfs*37]) and exon 8 (c.1398+2T>C) of the CYP11B1 gene leading both to a complete loss of function. The latter mutation has not yet been described in databases. 11ßOHD was identified by the measurement of 11-deoxycortisol in a newborn screening card of one patient retrospectively. Testicular adrenal rest tumours (TARTs) were detected in three patients at 3.7 years, 11 years and 14.4 years. Conclusion The diagnosis of CAH due to 11ßOHD is delayed and should be suspected in children with arterial hypertension, tall stature and precocious pseudopuberty. Patients may develop TARTs as early as infancy. 11ßOHD should be included in newborn screening programmes, at least in newborns of index families, to allow early diagnosis and the start of treatment to reduce morbidity.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Esteroide 11-beta-Hidroxilase/genética , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/genética , Hormônio Adrenocorticotrópico/sangue , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Mutação , Renina/sangue , Estudos Retrospectivos , Avaliação de SintomasRESUMO
Stroke outcome is determined by delayed neuronal cell death and edema formation. TWEAK, a cytokine of the TNF superfamily, and its membrane receptor Fn14 promote ischemia-induced neuronal apoptosis and leakage of the blood-brain barrier. Both TWEAK and Fn14 are upregulated in experimental stroke models. In this study, we investigated whether TWEAK and Fn14 are upregulated in stroke patients. We measured serum concentrations of TWEAK in stroke patients and matched control subjects by ELISA. Expression of Fn14 in the brain was evaluated by real-time RT-PCR and immunohistochemistry. TWEAK serum concentrations were elevated in stroke patients. In autopsy samples, we found elevated mRNA levels of the receptor Fn14 and a trend towards higher TWEAK mRNA levels. In the infarcted and peri-infarct tissue immunostaining for Fn14 was enhanced. These data show that the cytokine TWEAK and its membrane receptor Fn14 are upregulated in stroke and suggest that they contribute to stroke outcome.
Assuntos
Encéfalo/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Acidente Vascular Cerebral , Fatores de Necrose Tumoral/sangue , Regulação para Cima/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Citocina TWEAK , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Receptor de TWEAKRESUMO
BACKGROUND: Paediatric prolactinomas are rare. The aim of this study was to investigate the clinical features and outcome of paediatric patients with prolactinomas. METHODS: In this single-centre retrospective analysis, clinical, biochemical, and radiological features of all paediatric patients with pituitary adenomas diagnosed between 2000 and 2016 were evaluated. RESULTS: Among 21 patients with pituitary adenomas, 12 patients with prolactinomas (median age 14.2 years, range 11-16.6 years, 8 females, 4 males) were identified (7 macro- and 5 microprolactinomas). The most common clinical symptoms were headaches (67%) and pubertal delay (67%). All patients with macroprolactinomas with prolactin concentrations >10,000 mU/L had at least 1 pituitary hormone deficiency. Cabergoline as first-line treatment (n = 11, median follow-up of 37 months, range 12-89 months) induced normoprolactinemia (n = 8), reduced the mean tumour volume by 80%, and ameliorated headaches (p = 0.016) and pubertal delay (p = 0.031), whereas intermittent moderate side effects occurred in 55%. CONCLUSION: Adolescents with headaches and pubertal delay should be investigated for prolactinomas. Treatment with cabergoline is well tolerated and effective in reducing clinical symptoms and prolactin concentrations was well as inducing tumour shrinkage. Further clinical prospective studies are needed to standardize paediatric treatment modalities.
Assuntos
Neoplasias Hipofisárias/epidemiologia , Prolactinoma/epidemiologia , Adolescente , Antineoplásicos/uso terapêutico , Cabergolina , Criança , Ergolinas/uso terapêutico , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Estudos RetrospectivosRESUMO
The transcription factor nuclear factor kappaB (NF-kappaB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-kappaB has been demonstrated. To analyze which subunit of NF-kappaB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of the p52 or c-Rel gene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim and Noxa in cerebral ischemia depended on RelA and the upstream kinase IKK (IkappaB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-kappaB subunit RelA and may be mediated through Bim and Noxa.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Isquemia Encefálica/metabolismo , Proteínas de Membrana/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Fator de Transcrição RelA/biossíntese , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Isquemia Encefálica/genética , Células Cultivadas , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/biossíntese , NF-kappa B/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Transcrição RelA/deficiência , Fator de Transcrição RelA/genética , Transcrição Gênica/fisiologiaRESUMO
Gene regulation in sepsis is known to be controlled by the transcription factor NF-kappaB. However, the function of neuronal NF-kappaB in sepsis is not well defined. In a mouse model of sepsis induced by i.p. injection of lipopolysaccharides (LPS), we found an activation of NF-kappaB in the brain as shown by the induction of a transgenic NF-kappaB reporter. Inhibition of neuronal NF-kappaB by cell-specific expression of the NF-kappaB super-repressor IkappaBalpha-SR improved LPS-induced hypothermia and survival but had no effect on body weight or on the humoral response to LPS. In contrast, glial inhibition of NF-kappaB did not influence body temperature and survival. By immunohistochemistry, we detected the active NF-kappaB subunit RelA in neuronal nuclei of the organum vasculosum of the lamina terminalis. Our data reveal an important role of neuronal NF-kappaB in thermoregulation and survival. The upcoming group of NF-kappaB inhibitors may have a place in the treatment of the acute-phase response.
Assuntos
NF-kappa B/fisiologia , Inibição Neural/fisiologia , Sepse/mortalidade , Sepse/fisiopatologia , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hipotermia/induzido quimicamente , Hipotermia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , Inibição Neural/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Polissacarídeos/efeitos adversos , Sepse/induzido quimicamente , Sepse/patologia , Fatores de Tempo , TransfecçãoRESUMO
Non-selective and subunit (GluN2B)-specific N-methyl-d-aspartate receptor (NMDAR) antagonists represent promising alternative antidepressant drugs with fast onset of the therapeutic action. The neuronal activation pattern induced by NMDAR antagonists is well characterized by c-Fos expression analysis only in the adult rodent brain. In contrast, there is little information available regarding their effects during postnatal development. Here we performed a systematic c-Fos brain mapping of the non-selective NMDAR antagonist MK-801 and the GluN2B-specific antagonist Ro 25-6981 from postnatal day 16 (P16) to P40. We found significant regional differences with gender-specificity in the activation pattern compared to the adult. Surprisingly, in the hippocampus, MK-801 triggered at pre-pubertal stages (especially at P24) very strong c-Fos expression, followed by low levels after P30, the approximate time point of puberty onset in mice. The cortical distribution of MK-801-triggered c-Fos expression before puberty differed also substantially from the adult brain, showing high levels only in deep cortical layers at pre-pubertal stages. In comparison, the cortical activation induced by Ro 25-6981 diminished from high pre-pubertal levels and was in comparison with that triggered by MK-801 low in the hippocampus. These results reveal highly dynamic changes in the c-Fos activation pattern induced by NMDAR antagonists during puberty. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
Assuntos
Envelhecimento , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Córtex Cerebral/crescimento & desenvolvimento , Maleato de Dizocilpina/farmacologia , Feminino , Hipocampo/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenóis/farmacologia , Piperidinas/farmacologiaRESUMO
BACKGROUND: GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. AIMS: Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals. METHODS: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. RESULTS: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. CONCLUSIONS: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.
Assuntos
Loci Gênicos , Transtornos do Crescimento , Ossos Metacarpais , Pseudo-Hipoparatireoidismo , Adolescente , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/diagnóstico por imagem , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Humanos , Lactente , Masculino , Ossos Metacarpais/diagnóstico por imagem , Ossos Metacarpais/metabolismo , Tamanho do Órgão/genética , Pseudo-Hipoparatireoidismo/diagnóstico por imagem , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/metabolismo , RadiografiaRESUMO
BACKGROUND: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined. OBJECTIVE: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients. SUBJECTS/METHODS: 313 patients treated with GH, early [chronological age (CA) at GH start <12 years, n = 259] or late (CA at GH start ≥12 years, n = 54) who reached AH were selected from KIGS (Pfizer International Growth Database). RESULTS: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively. CONCLUSIONS: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start.
Assuntos
Estatura/efeitos dos fármacos , Hormônio do Crescimento Humano/administração & dosagem , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/fisiopatologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVES: An increased blood pressure can elicit remodeling of the cardiovascular system. Experimental data have implicated gp130, a subunit of the receptor for interleukin-6 (IL-6)-related cytokines, in the regulation of proliferation and apoptosis of cardiomyocytes and vascular smooth muscle cells (VSMC). Here, we investigate whether serum soluble gp130 concentrations correlate with blood pressure in humans, whether gp130 expression in the aorta differs between hypertensive and control rats, and whether angiotensin II or endothelin regulate gp130 expression in human VSMC. METHODS: We measured serum concentrations of soluble gp130, IL-6, the soluble IL-6 receptor, and the intima-media thickness of the common carotid artery in stroke patients (n = 48) and in elderly controls (n = 48). Furthermore, soluble gp130 levels were measured in young controls (n = 200). Expression of gp130 in Wistar-Kyoto (n = 12), spontaneously hypertensive rats (n = 12), and human VSMC was detected by real-time reverse transcription-PCR and immunohistochemistry. RESULTS: Soluble gp130 serum concentrations correlated with blood pressure in stroke patients and in elderly and young controls and with the intima-media thickness of the common carotid artery in stroke patients. The hypothesis that elevated soluble gp130 derives from the vascular system was supported by the enhanced expression of gp130 in the aortic wall of spontaneously hypertensive rats. Furthermore, treatment of human VSMC with angiotensin II stimulated gp130 expression. CONCLUSION: Our data suggest that soluble gp130 serum concentrations are correlated with blood pressure and may reflect vascular remodeling in response to arterial hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Receptor gp130 de Citocina/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensina II/farmacologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/metabolismo , Aorta Torácica/citologia , Aorta Torácica/metabolismo , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Determinação da Pressão Arterial/métodos , Artérias Carótidas/efeitos dos fármacos , Estudos de Casos e Controles , Técnicas de Cultura de Células , Células Cultivadas , Receptor gp130 de Citocina/sangue , Receptor gp130 de Citocina/metabolismo , Endotelina-1/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Especificidade da Espécie , Acidente Vascular Cerebral/metabolismo , Telemetria , Telmisartan , Fatores de Tempo , Túnica Íntima/patologia , Túnica Média/patologia , Vasoconstritores/farmacologia , Adulto JovemRESUMO
Cytokine-dependent mechanisms in the CNS have been implicated in the pathogenesis of depression. Interleukin-6 is upregulated in depressed patients and dowregulated by antidepressants. It is, however, unknown whether IL-6 is involved in the pathogenesis of depression. We subjected IL-6-deficient mice (IL-6(-/-)) to depression-related tests (learned helplessness, forced swimming, tail suspension, sucrose preference). We also investigated IL-6 in the hippocampus of stressed wild-type mice. IL-6(-/-) mice showed reduced despair in the forced swim, and tail suspension test, and enhanced hedonic behavior. Moreover, IL-6(-/-) mice exhibited resistance to helplessness. This resistance may be caused by the lack of IL-6, because stress increased IL-6 expression in wild-type hippocampi. This suggests that IL-6 is a component in molecular mechanisms in the pathogenesis of depression. IL-6(-/-) mice represent tools to study IL-6-dependent signaling pathways in the pathophysiology of depression in vivo. Moreover, these mice may support the screening of compounds for depression by altering cytokine-mediated signaling.