Combined Effects of Multiple Endoplasmic Reticulum Stresses on Cytokine Secretion in Macrophage

Cells show various stress signs when they are challenged with severe physiological problems. Majority of such cellular stresses are conveyed to endoplasmic reticulum (ER) and unfolded protein response (UPR) serves as typical defense mechanism against ER stress. This study investigated an interaction between ER stress agents using macropage cell line Raw 264.7. When activated by lipopolysaccharide (LPS), the cell lines showed typical indicators of ER stress. Along with molecular chaperones, the activation process leads to the production of additional infl ammatory mediators. Following activation, the macrophage cell line was further treated with TUN and characterized in terms of chaperone expression and cytokine secretion. When treated with TUN, the activated macrophage cell leads to increased secretion of IL-6 although expression of ER stress markers, GRP94 and GRP78 increased. The secretion of cytokines continued until the addition of BFA which inhibits protein targeting from ER to Golgi. However, secretion of cytokines was ceased upon dual treatments with BFA and TG. This result strongly implies that cells may differently deal with various polypeptides depending on the urgency in cellular function under ER stress. Considering IL-6 is one of the most important signal molecules in macrophage, the molecule might be able to circumvent ER stress and UPR to reach its targeting site.     

Chronic pancreatitis: Do serum biomarkers provide an association with an inflammageing phenotype?

BackgroundChronic pancreatitis is an inflammatory disorder of the pancreas that is associated with accelerated mortality for patients suffering from this disease. The association between chronic inflammation and accelerated biological ageing has been well described and is often referred to as “inflammageing”. In this review we seek to determine how systemic inflammation in chronic pancreatitis may contribute to an accelerated ageing phenotype.MethodsA systematic literature search with a predefined search protocol was performed on Medline, Embase and Cochrane libraries according to the PRISMA guidelines.ResultsThe initial search identified 499 studies. After title, abstract and full text screen of the search results, 20 were included for further evaluation. In the 20 remaining articles 41 inflammatory mediators were identified – mainly involved in chronic inflammation, fibrosis and particularly cardinal features of inflammageing such as sarcopenia and osteoporosis.ConclusionChronic pancreatitis is associated with elevated levels of inflammatory mediators many of which are associated with an accelerated ageing phenotype and may explain some of the clinical sequelae of this disease.     

Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms

Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated in the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women.     

ESTROGEN REGULATES CYTOKINE RELEASE IN HUMAN MAST CELLS

Estrogens are important for bone homeostasis and are classified as anti-resorptive agents. In ovariectomized rats, mast cell changes occurred during the activation of resorption. In addition, quantitative changes occurred in mast cell population residing near the site undergoing resorption. Considering these studies, mast cells may play a role in osteoporosis. Therefore, it is of paramount importance to study mast cell cytokine production also in the presence or absence of estrogen. When cultured in the absence of estrogen, human mast cells treated with PMA or A23187 demonstrated significantly greater release of TNF-α and IL-6 than cells grown under estrogen-depleted condition. Our results show that treatment of mast cells with estrogen prevented PMA or A23187-stimulated TNF-α or IL-6 release. These data provide evidence for a potent inhibition of cytokines by estrogen in human mast cells. This study may help to explain the association between mast cells and osteoporosis.     

The change in renal replacement therapy on acute renal failure in a general intensive care unit in a university hospital and its clinical efficacy: a Japanese experience

The aim of our study was to examine renal replacement therapies (RRT) that have been used for acute renal failure (ARF) in our intensive care unit (ICU) patients and to compare their outcomes. Sixteen patients who underwent intermittent hemodialysis (IHD), 14 patients who underwent continuous hemofiltration (CHF) in combination with IHD (CHF + IHD), and 38 patients who underwent continuous hemodiafiltration (CHDF) were evaluated. Regarding the effects of blood purification on hemodynamics and renal function, the percentage increase in blood pressure and percent rapid increase in urinary output were the greatest in the CHDF group. The hourly urinary output after the start of initial blood purification increased only in the CHDF group. The survival rate was significantly higher in the CHDF group. These results suggest that CHDF should be the first-line therapy for patients with ARF and that we are moving in the right direction regarding the application of RRT to treat ARF in ICU patients.     

细胞因子对正常甲状腺细胞cAMP生成的调节

目的　本文研究白介素１（ Ｉ Ｌ１） 、干扰素α（ Ｉ Ｆ Ｎα） 和肿瘤坏死因子（ Ｔ Ｎ Ｆ） 对人正常甲状腺细胞环磷酸腺苷（ｃ Ａ Ｍ Ｐ） 生成的影响。方法　运用人甲状腺细胞原代培养技术和放免分析技术，检测不同种类细胞因子刺激甲状腺细胞引起的ｃ Ａ Ｍ Ｐ 释放状况。结果　（１） Ｉ Ｌ１ 、 Ｉ Ｆ Ｎα和 Ｔ Ｎ Ｆ 均可促进甲状腺细胞基础ｃ Ａ Ｍ Ｐ 的释放。（２） Ｉ Ｌ１ 在１０ － ３ ～１０３ Ｕ／ｍｌ 的浓度范围内，可明显增强促甲状腺激素（ Ｔ Ｓ Ｈ） 对甲状腺细胞生成ｃ Ａ Ｍ Ｐ 的刺激效应，其中以１０ － １ Ｕ／ｍｌ 的 Ｉ Ｌ１ 作用最强。（３） Ｉ Ｆ Ｎα对 Ｔ Ｓ Ｈ 刺激甲状腺细胞ｃ Ａ Ｍ Ｐ 的生成具有双向调节作用，１０ － ２ ～１ Ｕ／ ｍｌ 可增加ｃ Ａ Ｍ Ｐ 释放，而１０３ Ｕ／ｍｌ 时则抑制 Ｔ Ｓ Ｈ 的刺激效应。（４）１０ ～１０４ Ｕ／ｍｌ 的 Ｔ Ｎ Ｆ 使 Ｔ Ｓ Ｈ 刺激甲状腺细胞生成ｃ Ａ Ｍ Ｐ 的量显著减少。结论　多种细胞因子参与甲状腺功能的调节，并可能与自身免疫性甲状腺疾病的发生发展过程有一定关联。     

儿童急性淋巴细胞白血病患者T淋巴细胞免疫功能的研究

目的 :研究儿童急性淋巴细胞白血病 (ALL)患者初治时和完全缓解 (CR)后外周血T淋巴细胞亚群及其分泌细胞因子的能力。方法 :采集B淋巴细胞系ALL儿童初治时、CR后的外周血 ,分离出其中的单个核细胞 (MNC)。用单克隆抗体在流式细胞仪上测定CD3、CD4、CD8以及IL 2受体CD2 5的含量 ;通过T淋巴细胞内细胞因子IFN γ和TNF α的测定 ,在单个细胞水平上分析T淋巴细胞功能的变化。结果 :①初治时 ,患者的CD4 /CD8为 (1.10± 0 .79) ,较健康儿童 (2 .74± 1.2 1)明显降低 (P <0 .0 1) ,CD4、CD8产生细胞因子IFN γ和TNF α的能力均低于正常对照 (P <0 .0 5 )。②CR后 ,CD4 /CD8为 2 .5 4± 1.39,比初治时明显提高 (P <0 .0 5 ) ,CD4、CD8产生细胞因子的能力增强 ,但与正常对照组相比 ,各项数值仍低。③初治患者的CD4 + CD2 5 + T淋巴细胞为 (0 .76± 0 .5 6 ) ,明显低于CR组 (2 0 .4± 5 .1) (P <0 .0 1)和对照组 (16 .3± 6 .3) (P <0 .0 1)。这表明 ,免疫损害在白血病的发病过程中起重要作用的细胞因子的产生和CD2 5都趋于正常。结论 :T淋巴细胞的免疫功能与儿童白血病的预后关系密切 ,促进患者免疫功能的恢复对本病的治疗非常重要     

Blueprint for schistosomiasis vaccine development

A number of different schistosome antigens are capable of partially protecting experimental animals from challenge infection. More than 100 such antigens have been identified, about 15% of which are strongly protective and deemed promising though they do not reach the level close to sterile immunity seen after vaccination with irradiated cercariae. Studies of human correlate reactions, i.e. serological reactions and cytokine responses to schistosomiasis antigens, in individuals living in areas endemic for schistosomiasis have shown associations between certain antigen-specific immune responses and lack of re-infection over time. This approach was applied in Brazil and Egypt where it was possible to epidemiologically follow cohorts of individuals in endemic areas for extended periods of time correlating infection status with immune responses against a panel of well-researched, highly purified vaccine candidates. The immune correlates found were unique to each antigen and could be either positive or negative, i.e. associated with resistance or with susceptibility to re-infection. However, few antigens were clear-cut in this respect, i.e. the majority of them induced ambiguous responses. For example, a single antigen might have a significant positive correlation when antigen-driven interferon (INF)-gamma production is measured but also show a significant negative correlation with respect to the IgG1 titre induced. These observations suggest that there are desirable, antigen-specific immune responses that would be valuable in a vaccine but they also indicate that there are responses that must be avoided. The insights gained should be useful not only for antigen selection but also for vaccine formulation prior to Phase I/II trials in humans. It would be of great value if similar independent, long-term human correlate studies could also be undertaken in areas endemic for Schistosoma japonicum.     

Evaluation of Apoptotic and Antileishmanial Activities of Artemisinin on Promastigotes and BALB/C Mice Infected with Leishmania major

Background:

In leishmaniasis, some drugs prescribed for treatment have toxic effects and there are reports about drug resistance in some countries. Due to this fact, using herbal drugs such as artemisinin with good efficacy and low toxic effect might be suitable.

Methods:

We evaluated the apoptotic effect of artemisinin on Leishmania major in vitro and the antileishmanial activities of artemisinin on leishmaniasis in BALB/c mice and at the end INF-γ and IL-4 cytokines levels were detected by ELISA in spleen cell culture supernatants. During treatment the lesion size and survival rate were measured each four and ten days, respectively.

Results:

Percentage of early and late apoptosis in promastigotes of control group and promastigotes treated with 10, 25, 50 and 100 μg/ml of artemisinin after 48 h were 0.13, 16.04, 41.23, 49.03 and 81.83, respectively. The IFN-γ in ointment treated group were higher than those of other groups (P<0.05). The in vivo results showed that ointment compounds healed the lesions more effectively rather than intraperitoneal injection method (P<0.05). The survival rate of mice 150 days after challenge in treated group with ointment of artemisinin was 66% while all mice in control groups were died.

Conclusion:

All of in vitro results represented that this drug had antileishmanial effects and these results were confirmed by evaluation effects in vivo condition of leishmaniasis. Interestingly, according to these results it can be concluded that this drug has antileishmanial effects in vitro and in vivo conditions. Artemisinin induces cytotoxic effect on L. major via apoptosis-related mechanism.