Mechanism of n-butanol alcohol extract of Baitouweng Decoction in treatment of vulvovaginal candidiasis based on negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis / 中国中药杂志

This study aimed to explore the mechanism of n-butanol alcohol extract of Baitouweng Decoction(BAEB) in the treatment of vulvovaginal candidiasis(VVC) in mice based on the negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis. In the experiment, female C57BL/6 mice were divided randomly into the following six groups: a blank control group, a VVC model group, high-, medium-, and low-dose BAEB groups(80, 40, and 20 mg·kg~(-1)), and a fluconazole group(20 mg·kg~(-1)). The VVC model was induced in mice except for those in the blank control group by the estrogen dependence method. After modeling, no treatment was carried out in the blank control group. The mice in the high-, medium-, and low-dose BAEB groups were treated with BAEB at 80, 40, and 20 mg·kg~(-1), respectively, and those in the fluconazole group were treated with fluconazole at 20 mg·kg~(-1). The mice in the VVC model group received the same volume of normal saline. The general state and body weight of mice in each group were observed every day, and the morphological changes of Candida albicans in the vaginal lavage of mice were examined by Gram staining. The fungal load in the vaginal lavage of mice was detected by microdilution assay. After the mice were killed, the degree of neutrophil infiltration in the vaginal lavage was detected by Papanicolaou staining. The content of inflammatory cytokines interleukin(IL)-1β, IL-18, and lactate dehydrogenase(LDH) in the vaginal lavage was tested by enzyme-linked immunosorbent assay(ELISA), and vaginal histopathology was analyzed by hematoxylin-eosin(HE) staining. The expression and distribution of NLRP3, PKCδ, pNLRC4, and IL-1Ra in vaginal tissues were measured by immunohistochemistry(IHC), and the expression and distribution of pNLRC4 and IL-1Ra in vaginal tissues were detected by immunofluorescence(IF). The protein expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by Western blot(WB), and the mRNA expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by qRT-PCR. The results showed that compared with the blank control group, the VVC model group showed redness, edema, and white secretions in the vagina. Compared with the VVC model group, the BAEB groups showed improved general state of VVC mice. As revealed by Gram staining, Papanicolaou staining, microdilution assay, and HE staining, compared with the blank control group, the VVC model group showed a large number of hyphae, neutrophils infiltration, and increased fungal load in the vaginal lavage, destroyed vaginal mucosa, and infiltration of a large number of inflammatory cells. BAEB could reduce the transformation of C. albicans from yeast to hyphae. High-dose BAEB could significantly reduce neutrophil infiltration and fungal load. Low-and medium-dose BAEB could reduce the da-mage to the vaginal tissue, while high-dose BAEB could restore the damaged vaginal tissues to normal levels. ELISA results showed that the content of inflammatory cytokines IL-1β, IL-18, and LDH in the VVC model group significantly increased compared with that in the blank control group, and the content of IL-1β, IL-18 and LDH in the medium-and high-dose BAEB groups was significantly reduced compared with that in the VVC model group. WB and qRT-PCR results showed that compared with the blank control group, the VVC model group showed reduced protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues of mice and increased protein and mRNA expression of NLRP3. Compared with the VVC model group, the medium-and high-dose BAEB groups showed up-regulated protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues and inhibited protein and mRNA expression of NLRP3 in vaginal tissues. This study indicated that the therapeutic effect of BAEB on VVC mice was presumably related to the negative regulation of NLRP3 inflammasome by promoting PKCδ/NLRC4/IL-1Ra axis.

Condición física e inflamatoria antes de una intervención quirúrgica mayor abdominal / Physical and inflammatory condition before major abdominal quirurgical intervention

Introducción: El desacondicionamiento físico se asocia con disminución en la capacidad cardiorrespiratoria, aumento en el contenido de grasa corporal, e imbalances en respuesta inflamatoria, todos ellos factor de riesgo frente a la agresión de una intervención quirúrgica mayor. El valor de consumo de oxígeno (VO2max), el índice de masa corporal (IMC) y los valores plasmáticos de citoquinas de pacientes programados para una intervención quirúrgica mayor abdominal a menudo no se tienen en cuenta en la valoración prequirúrgica. Objetivo: Determinar la condición física e inflamatoria de pacientes que se trataron con una intervención quirúrgica mayor abdominal. Métodos: Investigación cuantitativa, descriptiva. Muestra por conveniencia de pacientes que se trataron con una intervención quirúrgica mayor abdominal en dos hospitales de Manizales (Colombia). Previo a la intervención, se midió VO2max, el IMC y valores de citoquinas. Resultados: Participaron en el estudio 6 hombres y 48 mujeres. Los valores promedio del VO2max se categorizaron como bajos. Se encontraron valores altos de IMC, del receptor antagonista de IL-1 (IL-1 Ra) y del factor neutrotrófico derivado del cerebro (BDNF). No se hallaron diferencias significativas en los valores promedio de VO2max, de IL-1Ra y de BDNF entre los grupos. Los pacientes programados para intervención quirúrgica ginecológica y gastrointestinal tuvieron sobrepeso y los programados para intervención quirúrgica bariátrica fueron obesos mórbidos. Conclusión: Pacientes programados para una intervención quirúrgica mayor abdominal presentan valores bajos de VO2max para la edad y altos de IMC. Se hallaron valores altos de IL-1Ra y de BDNF asociadas a obesidad y a posible antiinflamación(AU)

Introduction: Physical deconditioning is associated with, a decrease in cardiorespiratory capacity, an increase in body fat content and imbalances in the inflammatory response, all of which are risk factors for the aggression of a major surgical intervention. The oxygen consumption value (VO2max), body mass index (BMI), and plasma cytokine values of patients scheduled for major abdominal surgery are often not taken into account in the presurgical evaluation. Objective: To determine the physical and inflammatory condition of patients who were treated with a major abdominal surgery. Methods: Quantitative, descriptive research. Convenience sample of patients who underwent major abdominal surgery in two hospitals in Manizales (Colombia). Prior to the intervention, VO2max, BMI and cytokine values were measured. Results: 6 men and 48 women participated in the study. Average VO2max values were categorized as low. High values of BMI, IL-1 receptor antagonist (IL-1 Ra) and brain derived neutrotrophic factor (BDNF) were found. No significant differences were found in the mean VO2max, IL-1Ra and BDNF values between the groups. Patients scheduled for gynecological and gastrointestinal surgery were overweight and those scheduled for bariatric surgery were morbidly obese. Conclusion: Patients scheduled for major abdominal surgery have low VO2max values for age and high BMI. High IL-1Ra and BDNF values were found associated with obesity and possible anti-inflammation(AU)

Significance of IL-1Ra and IL-6 gene variants in Turkish patients with Crimean-Congo hemorrhagic fever

Objective: To investigate the association between IL-1Ra variable number of tandem repeat (rs2234663), IL-6 -597GA (rs1800797), IL-6 -572GC (rs1800796) and the risk of Crimean-Congo hemorrhagic fever (CCHF) in the Turkish patients. Methods: This study included 50 patients infected with CCHF and 50 healthy controls. These variants were genotyped using polymerase chain reaction and/or restriction fragment length polymorphism method. Results:The distribution of the IL-6 -572GC genotypes and alleles varied significantly between the patients and the controls. The subjects carrying IL-6 -572GC GG genotype and G allele had increased risk of developing CCHF compared to the control group (P=0.006, P=0.014, respectively). IL-6 -572GC GC genotype was higher in the controls than the patients (P=0.006). For the triple genotype combinations, the 1/2-GC-GG genotype combination was detected more frequently in the control group than CCHF patients (P=0.016). IL-6 (-572/-597) GG-GG genotype was significantly higher in the patient group (P=0.015), while the GC-GG genotype was significantly lower in the patient group (P=0.005). Additionally, the G-G haplotype was significantly higher in the patient group (P=0.042), whereas C-G was found to be significantly lower in the patients than the control group (P=0.037). Conclusions: The results of this study suggest the IL-6 -572GC variant might be genetic markers of sensitivity to CCHF in the Turkish population and may facilitate greater protection against the disease.

Significance of IL-1Ra and IL-6 gene variants in Turkish patients with Crimean-Congo hemorrhagic fever

Objective: To investigate the association between IL-1Ra variable number of tandem repeat (rs2234663), IL-6 -597GA (rs1800797), IL-6 -572GC (rs1800796) and the risk of Crimean-Congo hemorrhagic fever (CCHF) in the Turkish patients. Methods: This study included 50 patients infected with CCHF and 50 healthy controls. These variants were genotyped using polymerase chain reaction and/or restriction fragment length polymorphism method. Results: The distribution of the IL-6 -572GC genotypes and alleles varied significantly between the patients and the controls. The subjects carrying IL-6 -572GC GG genotype and G allele had increased risk of developing CCHF compared to the control group (P=0.006, P=0.014, respectively). IL-6 -572GC GC genotype was higher in the controls than the patients (P=0.006). For the triple genotype combinations, the 1/2-GC-GG genotype combination was detected more frequently in the control group than CCHF patients (P=0.016). IL-6 (-572/-597) GG-GG genotype was significantly higher in the patient group (P=0.015), while the GC-GG genotype was significantly lower in the patient group (P=0.005). Additionally, the G-G haplotype was significantly higher in the patient group (P=0.042), whereas C-G was found to be significantly lower in the patients than the control group (P=0.037). Conclusions: The results of this study suggest the IL-6 -572GC variant might be genetic markers of sensitivity to CCHF in the Turkish population and may facilitate greater protection against the disease.

IL-1 Receptor Antagonist Reduced Chemical-Induced Keratinocyte Apoptosis through Antagonism to IL-1α/IL-1β

Extracellular interleukin 1 alpha (IL-1α) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-1α is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-1α and IL-1β mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-1α and IL-1β in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-1α and IL-1β, suggesting potential applications to predict skin irritation.

The beneficial effect of mesenchymal stem cells transplantation in combination with interleukin-1 receptor antagonist on post-hepatectomy liver failure / 中华肝胆外科杂志

Objective To study the synergetic effect and possible mechanism of transplanting mesenchymal stem cells (MSCs) in combination with interleukin-1 receptor antagonist (IL-1Ra) on acute liver failure (ALF).Methods MSCs transplantation combined with IL-1Ra was used for a swine model of ALF induced by 85％ total hepatectomy.The living conditions,blood samples and survival time were recorded or collected for analysis of hepatic function.Liver injury histology was analyzed.Hepatic cell regeneration and apoptosis were studied by immunohistochemistry staining of Ki67 and TUNELassays respectively.The expression levels of AKT and NF-κB were analyzed by Western blotting.Results The difference on the survival time between the model group and combined therapy group was statistically significant (P ＜ 0.05).Combined therapy displayed improvement not only in the serum biochemical conditions but also in the serum inflammatory cytokines.Furthermore,the observed hepatic histopathological score was significantly less compared to model group.In addition,the combined therapy group significantly inhibited the liver cell apoptosis and increased hepatic cell regeneration.Finally,a significant increase in AKT expression and decrease of NF-κB expression (P ＜ 0.05) were observed,which was consistent with their important roles in liver regeneration.Conclusion The combined therapy displayed a synergistic effect on liver regeneration,by promoting restoration and reconstruction of ALF,through regulation of inflammation and apoptosis signaling network.

The beneficial effect of mesenchymal stem cells transplantation in combination with interleukin-1 receptor antagonist on post-hepatectomy liver failure / 中华肝胆外科杂志

Objective To study the synergetic effect and possible mechanism of transplanting mesenchymal stem cells (MSCs) in combination with interleukin-1 receptor antagonist (IL-1Ra) on acute liver failure (ALF).Methods MSCs transplantation combined with IL-1Ra was used for a swine model of ALF induced by 85％ total hepatectomy.The living conditions,blood samples and survival time were recorded or collected for analysis of hepatic function.Liver injury histology was analyzed.Hepatic cell regeneration and apoptosis were studied by immunohistochemistry staining of Ki67 and TUNELassays respectively.The expression levels of AKT and NF-κB were analyzed by Western blotting.Results The difference on the survival time between the model group and combined therapy group was statistically significant (P ＜ 0.05).Combined therapy displayed improvement not only in the serum biochemical conditions but also in the serum inflammatory cytokines.Furthermore,the observed hepatic histopathological score was significantly less compared to model group.In addition,the combined therapy group significantly inhibited the liver cell apoptosis and increased hepatic cell regeneration.Finally,a significant increase in AKT expression and decrease of NF-κB expression (P ＜ 0.05) were observed,which was consistent with their important roles in liver regeneration.Conclusion The combined therapy displayed a synergistic effect on liver regeneration,by promoting restoration and reconstruction of ALF,through regulation of inflammation and apoptosis signaling network.

The effects of recombinant human interleukin-1 receptor antagonist on the cartilage repair in rat temporomandibular joint with osteoarthritis / 实用口腔医学杂志

Objective:To investigate the effects of recombinant human interluekin-1 receptor antogonist (rhIL-1Ra) on the cartilage repair in rat temporomandibular joint(TMJ) with osteoarthritis(OA).Methods:Collagenase-Ⅱ was injected into bilateral TMJs of 24 adult rats for the induction of bilateral TMJOA,1 week after injection,5μg rhIL-1Ra(diluted in 0.05 ml normal saline) was injected into each right TMJ and the left joint received the same amount of normal saline injection as the control.12 animals were sacrificed at 2and 4 weeks after the first injection respectively.HE staining,immunnohistochemical method and RT-PCR examination were conducted.Mankins scere was used to evaluate the TMJOA degree.1 adult SD rat was used as healthy control,and sacrificed at 2 weeks of the experiment.Results:The TMJs of both sides showed typical OA-related cartilage degradation 2 week after IL-1Ra treatment,the Mankin~ score of the IL-1Ra treated and control joints was 1.33±0.52 and 2.00±6.63 (P＞0.05),4 week after treatment that was 3.00± 0.63 and 6.50 ± 0.84 (P＜0.05),respectively.Lower expression of ADAMTS-4 and ADAMTS-5 was observed in the treated joints than in the controls (P＜0.05).Conclusion:Intra-articular injection of IL-1Ra into TMJ can alleviate the cartilage lesion,the mechanism may lie in the inhibition of the expression of ADAMTS-4 and ADAMTS-5.

Interleukin-1B (IL-1B-31 and IL-1B-511) and interleukin-1 receptor antagonist (IL-1Ra) gene polymorphisms in primary immune thrombocytopenia

BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated disease caused by autoantibodies against platelets membrane glycoproteins GPIIb/IIIa and GPIb/IX. The etiology of ITP remains unclear. This study evaluated the association of polymorphisms in interleukin (IL)-1B-31, IL-1B-511, and IL-1Ra with ITP. METHODS: Genotyping of IL-1B-31, IL-1B-511, and IL-1Ra was performed in 118 ITP patients and 100 controls by polymerase chain reaction restriction fragment length polymorphism and detection of variable number tandem repeats. RESULTS: Genotype differences in IL-1B-31 and IL-1Ra were significantly associated with ITP. Patients showed a higher frequency of the IL-1B-31 variant allele (T) and a 1.52-fold greater risk of susceptibility to ITP (odds ratio [OR]=1.52, 95% confidence interval [CI]=1.04–2.22, P=0.034). The frequencies of both homozygous and heterozygous variant genotypes of IL-1B-31 were higher (OR=2.33, 95% CI=1.069–5.09, P=0.033 and OR=2.044, 95% CI=1.068–39, P=0.034) among patients and were significantly associated with ITP susceptibility. Both homozygous and heterozygous variant genotypes of IL-1Ra were also more frequent (OR=4.48, 95% CI=1.17–17.05, P=0.0230 and OR=1.80, 95% CI=1.03–3.14, P=0.0494) among patients and were associated with ITP risk. IL-1B-31 and IL-1Ra also showed significant association with severe ITP. However, IL-1B-511 was not associated with ITP. CONCLUSION: IL-1B-31 and IL-1Ra polymorphisms may significantly impact ITP risk, and they could be associated with disease severity, which may contribute to the pathogenesis of ITP.

Effects of IL-1β on expression of AQP4 and its role in attack of seizure / 实用医学杂志

Objective To observe the effects of interleukin-1β (IL-1β) and pentylenetetrazol (PTZ) induced acute epilepsy and the dynamic expression of aquaporin-4 (AQP4) in hippocampus. To explore the role of IL-1β in the pathogenesis of epilepsy by regulating AQP4. Methods All rats were randomly divided into control group, IL-1β group, PTZ group, IL-1ra + PTZ group and dexamethasone + PTZ group. Observe the behavior of the rats within 60 minutes after injection and record seizure score in each group. Then immunohistochemistry and RT-qPCR were used to detect the expression of AQP4 at at 6 , 12, 24 and 36 h. Results Almost of rats in IL-1β group and PTZ group showed severe degree seizure. The rats in control group and dexamethasone + PTZ group showed no obvious seizure. The seizure of rats were more remarkable serious in PTZ group than that in the IL-1ra + pentylenetetrazole group (P < 0.05). Immunohistochemistry and RT-qPCR Show: the expression of AQP4 in hippocampus in PTZ group increased gradually after 12 h (P < 0.05), then reached in the peak after 24 h (P < 0.001). The expression of AQP4 in IL-1ra + PTZ group was lower compare with PTZ group in each time (P < 0.05). Although the expression of AQP4 in dexamethasone + PTZ group higher than the control group, it was not significantly different (P < 0.05). Conclusion The proinflammatory cytokine IL-1β break the balance of water in brain and increasing the concentration of extracellular excitatory amino acids or ions by upregulate the expression of AQP4 in order to promote the excitatory of neurons.

Research progress of biopharmaceuticals for type 2 diabetes mellitus / 中国药学杂志

OBJECTIVE: To summarize the research progress of biopharmaceuticals for type 2 diabetes mellitus. METHODS: Both pharmaceuticals being studied and the classical ones were classified and described, with newly published articles introduced. RESULTS: The research progress of biopharmaceuticals for T2DM was comprehensively summarized. CONCLUSION: The discovery of novel targets and pathogenic mechanism has made biopharmaceuticals a potent weapon for T2DM therapy, however, further optimization is needed and multiple problems still remain to be solved.

Profile of circulating levels of IL-1Ra, CXCL10/IP-10, CCL4/MIP-1β and CCL2/MCP-1 in dengue fever and parvovirosis

Dengue virus (DENV) and parvovirus B19 (B19V) infections are acute exanthematic febrile illnesses that are not easily differentiated on clinical grounds and affect the paediatric population. Patients with these acute exanthematic diseases were studied. Fever was more frequent in DENV than in B19V-infected patients. Arthritis/arthralgias with DENV infection were shown to be significantly more frequent in adults than in children. The circulating levels of interleukin (IL)-1 receptor antagonist (Ra), CXCL10/inducible protein-10 (IP-10), CCL4/macrophage inflammatory protein-1 beta and CCL2/monocyte chemotactic protein-1 (MCP-1) were determined by multiplex immunoassay in serum samples obtained from B19V (37) and DENV-infected (36) patients and from healthy individuals (7). Forward stepwise logistic regression analysis revealed that circulating CXCL10/IP-10 tends to be associated with DENV infection and that IL-1Ra was significantly associated with DENV infection. Similar analysis showed that circulating CCL2/MCP-1 tends to be associated with B19V infection. In dengue fever, increased circulating IL-1Ra may exert antipyretic actions in an effort to counteract the already increased concentrations of IL-1β, while CXCL10/IP-10 was confirmed as a strong pro-inflammatory marker. Recruitment of monocytes/macrophages and upregulation of the humoral immune response by CCL2/MCP-1 by B19V may be involved in the persistence of the infection. Children with B19V or DENV infections had levels of these cytokines similar to those of adult patients.

Expression of NF-κB and IL-1ra in Gastric Cancer and Its Clinical Significance / 中山大学学报(医学科学版)

[Objective] To investigate the expression of NF-κB and IL-lra in gastric cancer, and to explore their correlation with the clinicopathological parameters and prognosis of gastric cancer (GC). [Methods] Expression of NF-κB and IL-1ra was detected by immunohistochemistry in tissue microarry of 359 cases of GC. [Results] The expression rates of NF-κB in the patients with metastasis of lymph node, TNM Ⅲ-Ⅳ stage, and poorly differentiated of histology were 80.2%, 80.0%, and 79.2%, respectively. The expression rates of IL-1ra in the patients with tumor size ≤3 cm, early stage, non-metastasis of lymph node, and TNM Ⅰ-Ⅱ stage were 61.7%, 75.0%, 66.4%, and 61.9%, respectively. The 5-year survival rate of the cases with non-expressed NF-κB was statistically higher than that of the cases with expressed NF-κB(P=0.036). The 5-year survival rate of the patients with negative expression of NF-κB and positive expression of IL-1ra was statistically higher than the others (P=0.021). [Conclusions] NF-κB is the adverse predictors of prognosis of gastric cancer. IL-1ra maybe play a protective role in early gastric cancer stage, but it is necessary to study deeply and get more evidences.

Changes of IL-1β and IL-1ra expression in the hippocampus of rats with frequent febrile seizures / 中国小儿急救医学

Objective To evaluate the changes of IL-1β and IL-lra in hippocampus of rats with frequent febrile seizures(FS).Methods 21-day-old male Sprague-Dawley(SD)rats were randomly divided into 3 groups:normal control group(NC group),hyperthermic control group(HC group)and febrile seizures group(FS group).IL-1β and IL-1ra levels in hippocampus of these rats were determined by ELISA methods,IL-1β mRNA and IL-1ra mRNA levels in hippocampus were measured by RT-PCR.Results IL-1β mRNA and protein levels in hippocampus of rats in FS group were significantly higher than those in NC group and HC group(P＜0.01,P＜0.05).IL-1ra mRNA and protein levels in hippocampus of rats in FS group were significantly higher than those in NC group and HC group(P＜0.01,P＜0.05),too.IL-1ra/IL-1β protein ratio showed no significant difference among 3 groups.Conclusion Frequent FS can cause the increase of IL-1β and IL-lra mRNA and protein levels in hippocampus,suggesting that IL-1β and IL-1ra may be involved in the pathogenesis of hippocampal neuron damage in FS rat.

Avaliação da expressão de interleucina 1 beta (IL-1 beta) e antagonista do receptor de interleucina 1 (IL-1Ra) em pacientes com hanseníase / Evaluation of the expression of interleukin 1 beta(IL-1 beta) and interleukin 1 receptor antagonist (IL-1Ra) in leprosy patients

A hanseníase é uma doença infectocontagiosa espectral que acompanha-se por uma série de eventos imunológicos desencadeados pela resposta do hospedeiro frente ao agente etiológico, o Mycobacterium leprae. Evidências sugerem que a indução e manutenção da resposta imune/inflamatória na hanseníase estão vinculadas a interações de múltiplas células e fatores solúveis, particularmente através da ação de citocinas. Nesse estudo, foram mensurados níveis de IL-1β e IL-1Ra de 37 casos novos de hanseníase acompanhados ao longo do tratamento e 30 controles sadios pelo teste ELISA. A coleta de sangue periférico foi realizada em quatro tempos para os casos de hanseníase (pré-tratamento com PQT, 2ª dose, 6ª dose e pós-PQT) e em único momento para os controles. Na comparação dos níveis das moléculas de casos no pré-PQT e controles, houve diferença estatisticamente significativa somente para IL-1β. Nossos resultados sugerem a participação dessa citocina no processo imune/inflamatório.

Leprosy is an infectious and contagious spectral disease accompanied by a series of immunological events triggered by the host's response to the etiologic agent, Mycobacterium leprae. Evidence suggests that the induction and maintenance of the immune/inflammatory response in leprosy are linked to multiple cell interactions and soluble factors, mainly through the action of cytokines. The ELISA test was used to measure the levels of IL-1β and IL-1Ra in 37 new leprosy patients followed-up during treatment and 30 healthy controls. Peripheral blood was collected four times during the treatment of leprosy patients (MDT pretreatment, 2nd dose, 6th dose and post-MDT), and only once from the controls. The comparison of molecular levels in pre-MDT patients and controls showed a statistically significant difference for IL-1β. The results suggest the participation of this cytokine in the genesis of the immune/inflammatory process.

IL-1Ra Elaboration by Colchicine Stimulation in Normal Human Bronchial Epithelial Cells / 결핵및호흡기질환

BACKGROUND: Asthma is a syndrome that is characterized by a variable degree of airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Colchicine is an inexpensive and safe medication with unique anti- inflammatory properties. IL-1Ra (Interleukin-1 receptor antagonist) mediates the anti-inflammatory effect in human inflammatory diseases, including asthma. This study examined whether IL-1Ra mediates the anti-inflammatory effect of colchicine in normal human bronchial epithelial cells (NHBE), RAW 264.7 cells (murine macrophage cell line), and a mouse lung. METHODS: NHBE, RAW 264.7 cells and BALB/c mice were stimulated with colchicine, and the increase in the IL-1Ra level was estimated by ELISA, Western analysis and RT-PCR analysis. RESULTS: Colchicine stimulated NHBE and RAW 264.7 cells to release IL-1Ra into the supernatant in a dose-and time-dependent manner. The major isoform of IL-1Ra in NHBE and RAW 264.7 cells is type I icIL-1Ra, and sIL-1Ra, respectively. IL-1Ra up-regulation was blocked by PD98059, a specific inhibitor in MAPK pathways. Colchicine also stimulated the secretion of IL-1Ra into the bronchoalveolar lavage (BAL) fluid of BALB/c mouse. CONCLUSION: Colchicine stimulates an increase in the IL-1Ra level both in vivo and in vitro, and might have an anti-inflammatory effect.

IL-1Ra Elaboration by Colchicine Stimulation in Normal Human Bronchial Epithelial Cells / 결핵및호흡기질환

BACKGROUND: Asthma is a syndrome that is characterized by a variable degree of airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Colchicine is an inexpensive and safe medication with unique anti- inflammatory properties. IL-1Ra (Interleukin-1 receptor antagonist) mediates the anti-inflammatory effect in human inflammatory diseases, including asthma. This study examined whether IL-1Ra mediates the anti-inflammatory effect of colchicine in normal human bronchial epithelial cells (NHBE), RAW 264.7 cells (murine macrophage cell line), and a mouse lung. METHODS: NHBE, RAW 264.7 cells and BALB/c mice were stimulated with colchicine, and the increase in the IL-1Ra level was estimated by ELISA, Western analysis and RT-PCR analysis. RESULTS: Colchicine stimulated NHBE and RAW 264.7 cells to release IL-1Ra into the supernatant in a dose-and time-dependent manner. The major isoform of IL-1Ra in NHBE and RAW 264.7 cells is type I icIL-1Ra, and sIL-1Ra, respectively. IL-1Ra up-regulation was blocked by PD98059, a specific inhibitor in MAPK pathways. Colchicine also stimulated the secretion of IL-1Ra into the bronchoalveolar lavage (BAL) fluid of BALB/c mouse. CONCLUSION: Colchicine stimulates an increase in the IL-1Ra level both in vivo and in vitro, and might have an anti-inflammatory effect.

Changes in the Serum Interleukin 6 Levels after Rehabilitation Exercise and Hot Spring Bathing in Patients with Rheumatoid Arthritis / 日本温泉気候物理医学会雑誌

We have previously reported that a depressive mental state of the patients with rheumatoid arthritis (RA) could be improved by rehabilitation exercise and hot spring bathing. These patients noticed that their muscle stiffness decreased and that they also felt mentally refreshed. In this study, the changes in the serum inflammatory cytokine levels after rehabilitation exercise and hot spring bathing in the RA patients with an active disease were evaluated and increased levels of interleukin 6 (IL-6) were found to decrease to the nearly half of the pre exercise levels. The decreases in the IL-6 levels were not attributed to the circadian rhythm and they also did not correlate with the serum cortisole levels. Next, we chose RA patients with active disease who had not been treated with any corticosteroids or exercise therapy. After exercise, the patients tended to complain of aggravated muscle stiffness and joint pain as well as discomfort. Their IL-6 levels did not show any decrease, but instead a moderate increase was observed. IL-1 receptor antagonist (IL-1ra) showed normal levels before exercise, and they did not change substantially after the exercise. As a result, when patients with active disease achieved a decrease in muscle stiffness and also felt refreshed, then their serum IL-6 levels also decreased. Such exercise therapy should be initiated when the patients' complaints have improved owning to sufficient bed rest and small doses of corticosteroids.

Interleukin 1 Receptor Antagonist(IL-1ra) Gene Polymorphism in Children with Henoch-Schonlein Purpura Nephritis

PURPOSE: Interleukin 1 receptor antagonist(IL-1ra) is an endogenous antiinflammatory agent that binds to IL-1 receptor and thus competitively inhibits the binding of IL-1alpha and IL-1beta. Allele 2 in association with various autoimmune diseases has been reported. In order to evaluate the influence of IL-1ra gene VNTR polymorphism on the susceptibility to HSP and its possible association with disease severity, manifested by severe renal involvement and renal sequelae, we studied the incidence of carriage rate and allele frequency of the 2 repeats of IL-1ra allele 2(IL1RN*2) of the IL-1ra gene in children with HSP with and without renal involvement. METHODS: The IL-1ra gene polymorphisms were determined in children with HSP with(n= 40) or without nephritis(n=34) who had been diagnosed at Busan Paik Hospital and the control groups(n=163). Gene polymorphism was identified by PCR amplification of the genomic DNA. RESULTS: The allelic frequency and carriage rate of IL1RN*1 were found most frequently in patients with HSP and in controls. The allelic frequency of IL1RN*2 was higher in patients with HSP compared to that of controls(4.7% vs. 2.5%, P=0.794). The carriage rate of IL1RN*2 was higher in patients with HSP compared to that of controls(8.1% vs. 6.8%, P= 0.916). The allelic frequency of IL1RN*2 was higher in patients with HSP nephritis compared to that of HSP(6.3% vs.2.9%, P=0.356). The carriage rate of IL1RN*2 was higher in patients with HSP nephritis compared to that of HSP(10.0% vs. 5.9%, P=0.523). Among 13 patients with heavy proteinuria(>1.0 g), 11 had IL1RN*1, 1 had IL1RN*2 and the others had IL1RN*4. At the time of last follow up 4 patients had sustained proteinuria and their genotype was IL1RN*1. CONCLUSION: The allelic frequency and carriage rate of IL1RN*1 were found most frequently in patients with HSP and in controls. Our study suggests that the carriage rate and allele frequency of the 2-repeats of IL-1ra allele 2(IL1RN*2) of the IL-1ra gene may not be associated with susceptibility and severity of renal involvement in children with HSP.

IL-1beta and IL-1 Receptor Antagonist Gene Polymorphisms in Myasthenia Gravis

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder characterized by an immune response against the nicotinic acetylcholine receptor at the neuromuscular junction. Genetic factors as well as abnormalities of immune regulation can increase the likelihood of MG. Proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, and their receptor antagonist (IL-1Ra) play major roles in initiating and modulating immune responses. The aim of the present study was to analyze IL-1beta and IL-1 Ra gene polymorphisms between MG patients and healthy controls. METHODS: TaqI restriction fragment polymorphism (RFLP) in exon 5 of IL-1beta and variable numbers of an 86-bp tandem repeat (VNTR) in intron 2 of IL-1Ra were analyzed in 80 patients with MG and 94 matched healthy control individuals. RESULTS: In IL-1beta TaqI RFLP, the genotype of A1/A1 and A1/A2 were 92.5% and 7.5% in patients with MG. In healthy controls, the frequencies of each genotype were 93.6% and 6.4% respectively. IL-1Ra polymorphism, the genotypes of A1/A1, A1/A2 and A1/A3 were 81.3%, 16.3%, and 2.5% in patients with MG. In healthy controls, the frequencies of each genotype were 87.2%, 7.4% and 3.2% respectively. There was no significant difference in the genotype frequencies of IL-1beta TaqI RFLP and IL-1Ra polymorphism between patients and the control group. CONCLUSIONS: These data suggested that the IL-1beta and IL-1Ra gene polymorphisms may not be associated with MG. However, further study is needed to clarify the possible role of IL-1beta and IL-1Ra gene polymorphisms in the susceptibility to myasthenia gravis.