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1.
Scand J Work Environ Health ; 49(5): 341-349, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37096788

RESUMO

OBJECTIVES: Patients with idiopathic inflammatory rheumatic diseases (IIRD) often have decreased working capacity resulting in indirect costs. However, data on patients' short-term sick leave has been limited. This retrospective cohort study evaluated the number and length of sick leave, including short-term leave, and occupational healthcare resource utilization (HCRU) of the working-aged patients with IIRD compared to controls. METHODS: The data on sick leave and occupational HCRU were gathered from the electronic medical records of the largest occupational healthcare provider in Finland from January 2012 to December 2019. Employed patients with an IIRD (including rheumatoid arthritis, spondyloarthritis, psoriatic and enteropathic arthritis, juvenile arthritis, and reactive arthritis) with at least a 12-months follow-up were identified and compared to age-, sex-, and follow-up matched controls without IIRD. RESULTS: Altogether 5405 patients with IIRD were identified and compared with an equal number of controls. The patients incurred approximately 2.5 times more sick leave than controls: 21.7 versus 8.5 days per patient year, respectively. Short-term sick leave was common: 83% of sickness absence periods of the patients lasted 1-9 days and represented 30% of the total absenteeism. Loss of productivity due to lost workdays was on average €4572 (95% confidence interval €4352-4804) per patient year. Occupational HCRU was approximately 1.8 times higher among IIRD patients than controls. CONCLUSIONS: Workers with an IIRD incur considerably more sick leave and use more occupational healthcare services than controls. Short sick leave not registered in national insurance registers constitute a significant portion of days off work among patients with IIRD.


Assuntos
Doenças Profissionais , Osteoartrite , Humanos , Idoso , Estudos Retrospectivos , Absenteísmo , Emprego , Licença Médica , Atenção à Saúde
2.
PLoS Pathog ; 5(3): e1000324, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19266083

RESUMO

Host signal-transduction pathways are intimately involved in the switch between latency and productive infection of herpes viruses. As with other herpes viruses, infection by Kaposi's sarcoma herpesvirus (KSHV) displays these two phases. During latency only few viral genes are expressed, while in the productive infection the virus is reactivated with initiation of extensive viral DNA replication and gene expression, resulting in production of new viral particles. Viral reactivation is crucial for KSHV pathogenesis and contributes to the progression of KS. We have recently identified Pim-1 as a kinase reactivating KSHV upon over-expression. Here we show that another Pim family kinase, Pim-3, also induces viral reactivation. We demonstrate that expression of both Pim-1 and Pim-3 is induced in response to physiological and chemical reactivation in naturally KSHV-infected cells, and we show that they are required for KSHV reactivation under these conditions. Furthermore, our data indicate that Pim-1 and Pim-3 contribute to viral reactivation by phosphorylating the KSHV latency-associated nuclear antigen (LANA) on serine residues 205 and 206. This counteracts the LANA-mediated repression of the KSHV lytic gene transcription. The identification of Pim family kinases as novel cellular regulators of the gammaherpesvirus life cycle facilitates a deeper understanding of virus-host interactions during reactivation and may represent potential novel targets for therapeutic intervention.


Assuntos
Antígenos Virais/metabolismo , Herpesvirus Humano 8/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ativação Viral , Latência Viral , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-pim-1/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Células Vero , Replicação Viral
3.
J Leukoc Biol ; 82(3): 710-20, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17595377

RESUMO

Macrophages and dendritic cells (DC) are APC, which regulate innate and adaptive immune responses. Macrophages function locally mainly, maintaining inflammatory responses in tissues, whereas DC take up microbes, mature, and migrate to local lymph nodes to present microbial antigens to naïve T cells to elicit microbe-specific immune responses. Blood monocytes can be differentiated in vitro to macrophages or DC by GM-CSF or GM-CSF + IL-4, respectively. In the present study, we performed global gene expression analyses using Affymetrix HG-U133A Gene Chip oligonucleotide arrays during macrophage and DC differentiation. During the differentiation process, 340 and 350 genes were up-regulated, and 190 and 240 genes were down-regulated in macrophages and DC, respectively. There were also more that 200 genes, which were expressed differentially in fully differentiated macrophages and DC. Macrophage-specific genes include, e.g., CD14, CD163, C5R1, and FcgammaR1A, and several cell surface adhesion molecules, cytokine receptors, WNT5A and its receptor of the Frizzled family FZD2, fibronectin, and FcepsilonR1A were identified as DC-specific. Our results reveal significant differences in gene expression profiles between macrophages and DC, and these differences can partially explain the functional differences between these two important cell types.


Assuntos
Biomarcadores/metabolismo , Diferenciação Celular/genética , Células Dendríticas/metabolismo , Perfilação da Expressão Gênica , Macrófagos/citologia , Monócitos/citologia , Western Blotting , Linhagem da Célula , Células Cultivadas , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Macrófagos/metabolismo , Monócitos/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5a
4.
J Leukoc Biol ; 79(6): 1279-85, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16551679

RESUMO

Dendritic cells (DCs) play an important role in innate and adaptive immune responses. In addition to their phagocytic activity, DCs present foreign antigens to naïve T cells and regulate the development of adaptive immune responses. Upon contact with DCs, activated T cells produce large quantities of cytokines such as interferon-gamma (IFN-gamma) and interleukin (IL)-21, which have important immunoregulatory functions. Here, we have analyzed the effect of IL-21 and IFN-gamma on lipopolysaccharide (LPS)-induced maturation and cytokine production of human monocyte-derived DCs. IL-21 and IFN-gamma receptor genes were expressed in high levels in immature DCs. Pretreatment of immature DCs with IL-21 inhibited LPS-stimulated DC maturation and expression of CD86 and human leukocyte antigen class II (HLAII). IL-21 pretreatment also dramatically reduced LPS-stimulated production of tumor necrosis factor alpha, IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) but not that of CXCL8. In contrast, IFN-gamma had a positive feedback effect on immature DCs, and it enhanced LPS-induced DC maturation and the production of cytokines. IL-21 weakly induced the expression Toll-like receptor 4 (TLR4) and translation initiation region (TIR) domain-containing adaptor protein (TIRAP) genes, whereas the expression of TIR domain-containing adaptor-inducing IFN-beta (TRIF), myeloid differentiation (MyD88) 88 factor, or TRIF-related adaptor molecule (TRAM) genes remained unchanged. However, IL-21 strongly stimulated the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3 genes. SOCS are known to suppress DC functions and interfere with TLR4 signaling. Our results demonstrate that IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid DCs, providing a negative feedback loop between DCs and T lymphocytes.


Assuntos
Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/farmacologia , Proteínas Repressoras/biossíntese , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Linfócitos T/metabolismo , Comunicação Celular , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Células Cultivadas/metabolismo , Quimiocina CCL5 , Quimiocinas CC/biossíntese , Quimiocinas CC/genética , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Citocinas/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Antígenos HLA-DR/biossíntese , Humanos , Interferon gama/farmacologia , Interleucina-12/biossíntese , Interleucina-12/genética , Subunidade alfa de Receptor de Interleucina-21 , Interleucinas/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/antagonistas & inibidores , Ativação Linfocitária , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Interferon/biossíntese , Receptores de Interferon/genética , Receptores de Interleucina/biossíntese , Receptores de Interleucina/genética , Receptores de Interleucina-1/biossíntese , Receptores de Interleucina-1/genética , Receptores de Interleucina-21 , Proteínas Recombinantes/farmacologia , Proteínas Repressoras/genética , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T/imunologia , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Receptor de Interferon gama
5.
J Leukoc Biol ; 71(3): 511-9, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11867689

RESUMO

GM-CSF signals through JAK2 and STAT5 and stimulates the expression of STAT5 target genes, such as pim-1 and CIS. Analyzed by EMSA, GM-CSF stimulation led to much stronger STAT5 DNA-binding to pim-1 or CIS GAS elements in primary human monocytes compared with mature macrophages. Similarly, GM-CSF-induced expression of pim-1 and CIS mRNAs was much stronger in monocytes. These differencies were not a result of downregulation of the GM-CSF receptor system or STAT5 expression, because monocytes and macrophages readily expressed GM-CSF receptor, JAK2, STAT5A, and STAT5B mRNAs and proteins. Monocytes expressed significant amounts of truncated STAT5 forms that took part in STAT5-DNA complex formation in GM-CSF-stimulated monocytes. This resulted in faster moving STAT5 complexes compared with macrophages in EMSA. Our results demonstrate that STAT5 isoform expression, GM-CSF-induced STAT5 activation, and STAT5 target-gene expression are altered significantly during monocyte/macrophage differentiation.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/fisiologia , Proteínas do Leite , Monócitos/fisiologia , Transativadores/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Macrófagos/citologia , Monócitos/citologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-pim-1 , Fator de Transcrição STAT5 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina , Proteínas Supressoras de Tumor
7.
J Immunol ; 178(1): 253-61, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17182562

RESUMO

CCL19 chemokine has a central role in dendritic cell (DC) biology regulating DC traffic and recruitment of naive T cells to the vicinity of activated DCs. In this study, we have analyzed the regulation of CCL19 gene expression in human monocyte-derived DCs. DCs infected with Salmonella enterica or Sendai virus produced CCL19 at late times of infection. The CCL19 promoter was identified as having two putative NF-kappaB binding sites and one IFN-stimulated response element (ISRE). Transcription factor binding experiments demonstrated that Salmonella or Sendai virus infection increased the binding of classical p50+p65 and alternative p52+RelB NF-kappaB proteins to both of the CCL19 promoter NF-kappaB elements. Interestingly, Salmonella or Sendai virus infection also increased the binding of multiple IFN regulatory factors (IRFs), STAT1, and STAT2, to the ISRE element. Enhanced binding of IRF1, IRF3, IRF7, and IRF9 to the CCL19 promoter ISRE site was detected in Salmonella or Sendai virus-infected cell extracts. The CCL19 promoter in a luciferase reporter construct was activated by the expression of NF-kappaB p50+p65 or p52+RelB dimers. IRF1, IRF3, and IRF7 proteins also activated CCL19 promoter in the presence of Sendai virus infection. CCL19 promoter constructs mutated at NF-kappaB and/or ISRE sites were only weakly activated. Ectopic expression of RIG-I (DeltaRIG-I, CARDIF) or TLR3/4 (TRIF, MyD88, IKKepsilon, or TBK1) signaling pathway components induced CCL19 promoter activity, suggesting that these pathways are important in CCL19 gene expression. Our experiments reveal that expression of the CCL19 gene is regulated by a combined action of several members of the NF-kappaB, IRF, and STAT family transcription factors.


Assuntos
Quimiocinas CC/genética , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Bases , Quimiocina CCL19 , Quimiocina CCL20 , Quimiocina CXCL10 , Quimiocinas CXC/genética , Citocinas/metabolismo , Proteína DEAD-box 58 , RNA Helicases DEAD-box/metabolismo , Células Dendríticas/microbiologia , Humanos , Interferon gama/metabolismo , Proteínas Inflamatórias de Macrófagos/genética , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Receptores Imunológicos , Elementos de Resposta , Salmonella enterica/imunologia , Vírus Sendai/imunologia , Transdução de Sinais , Receptores Toll-Like/metabolismo , Transcrição Gênica
8.
J Immunol ; 175(10): 6570-9, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16272311

RESUMO

In vitro human monocyte differentiation to macrophages or dendritic cells (DCs) is driven by GM-CSF or GM-CSF and IL-4, respectively. IFN regulatory factors (IRFs), especially IRF1 and IRF8, are known to play essential roles in the development and functions of macrophages and DCs. In the present study, we performed cDNA microarray and Northern blot analyses to characterize changes in gene expression of selected genes during cytokine-stimulated differentiation of human monocytes to macrophages or DCs. The results show that the expression of IRF4 mRNA, but not of other IRFs, was specifically up-regulated during DC differentiation. No differences in IRF4 promoter histone acetylation could be found between macrophages and DCs, suggesting that the gene locus was accessible for transcription in both cell types. Computer analysis of the human IRF4 promoter revealed several putative STAT and NF-kappaB binding sites, as well as an IRF/Ets binding site. These sites were found to be functional in transcription factor-binding and chromatin immunoprecipitation experiments. Interestingly, Stat4 and NF-kappaB p50 and p65 mRNAs were expressed at higher levels in DCs as compared with macrophages, and enhanced binding of these factors to their respective IRF4 promoter elements was found in DCs. IRF4, together with PU.1, was also found to bind to the IRF/Ets response element in the IRF4 promoter, suggesting that IRF4 protein provides a positive feedback signal for its own gene expression in DCs. Our results suggest that IRF4 is likely to play an important role in myeloid DC differentiation and gene regulatory functions.


Assuntos
Células Dendríticas/imunologia , Fatores Reguladores de Interferon/genética , Macrófagos/imunologia , Animais , Sequência de Bases , Northern Blotting , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , DNA/metabolismo , DNA Complementar/genética , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Retroalimentação , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Dados de Sequência Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , NF-kappa B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Especificidade da Espécie , Fator de Necrose Tumoral alfa/farmacologia
9.
J Immunol ; 170(11): 5464-9, 2003 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12759422

RESUMO

NK and T cell-derived IFN-gamma is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-gamma, T-bet, IL-12R beta 2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-gamma gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-gamma mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-gamma gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-gamma gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-gamma production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-gamma gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-gamma gene regulatory sites. IL-18, however, activated the binding of NF-kappa B to the IFN-gamma promoter NF-kappa B site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response.


Assuntos
Adjuvantes Imunológicos/fisiologia , Interferon gama/biossíntese , Interleucina-15/fisiologia , Interleucina-18/fisiologia , Interleucinas/fisiologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Adjuvantes Imunológicos/antagonistas & inibidores , Linhagem Celular , Células Cultivadas , Citocinas/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Humanos , Fatores Reguladores de Interferon , Interferon gama/genética , Interleucina-15/antagonistas & inibidores , Interleucinas/antagonistas & inibidores , Células Matadoras Naturais/metabolismo , NF-kappa B/metabolismo , Fosforilação , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT1 , Fator de Transcrição STAT4 , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , Transativadores/fisiologia , Tirosina/metabolismo
10.
Cytokine ; 24(3): 81-90, 2003 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-14581002

RESUMO

IFN-alpha and IL-12 are macrophage-derived cytokines that enhance innate and Th1 immune responses. However, there is little information regarding IFN-alpha and IL-12 target genes that would be involved in mediating the immunostimulatory effects of these cytokines. The interferon regulatory factor (IRF) family of transcription factors is known to be involved in controlling lymphocyte differentiation and functions. In this work we have studied the effect of IFN-alpha and IL-12 on the expression of IRF transcription factors in human NK and T cells. Both IFN-alpha and IL-12 strongly up-regulated IRF-1, IRF-4, and IRF-8 mRNA and protein expression. The binding of IRF-4 and IRF-8 to the lambdaB gene enhancer sequence was also increased following IFN-alpha- and IL-12-treatment of NK and T cells. A GAS element from the promoter region of the IRF-4 gene was identified. Following stimulation of cells with IFN-alpha or IL-12, Stat4 was found to bind to this IRF-4 GAS element, as detected by EMSA and DNA affinity binding, implying that the IRF-4 gene is directly activated by both cytokines. Our results suggest that IFN-alpha and IL-12 may enhance innate and Th1 immune responses by inducing IRF-1, IRF-4, and IRF-8 gene expression.


Assuntos
Proteínas de Ligação a DNA/genética , Interferon-alfa/farmacologia , Interleucina-12/farmacologia , Fosfoproteínas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sítios de Ligação , Polaridade Celular , Células Cultivadas , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Fator Regulador 1 de Interferon , Fatores Reguladores de Interferon , Interferon-alfa/metabolismo , Interleucina-12/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT4 , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/efeitos dos fármacos
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