Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

Alpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely play a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide). In vivo treatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore, in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.     

PACAP deficiency aggravates atherosclerosis in ApoE deficient mice

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays an important role in cytoprotection, inflammation and cardiovascular regulation. Thus, we studied the involvement of PACAP in atherogenesis. Differentiated human THP-1 macrophages (MΦ) were stimulated with oxidized low-density lipoproteins (oxLDL) and the influence of PACAP38 treatment on lipid content and TNF release was determined. To test the effect of PACAP deficiency (PACAP^?/?) on the development of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP^?/? mice were crossbred with ApoE^?/? to generate PACAP^?/?/ApoE^?/? mice. Blood cholesterol and triglyceride levels were quantified. Lumen stenosis in the brachiocephalic trunk, cellularity and amounts of pro-inflammatory as well as autophagy-, apoptosis- and necroptosis-relevant proteins were analysed in atherosclerotic plaques by quantitative immunohistochemistry. In vitro, PACAP38 inhibited oxLDL-induced intracellular lipid storage as well as TNF release in MФ. In vivo, after SC, but not under CED, PACAP^?/?/ApoE^?/? mice showed an increased lumen stenosis compared to ApoE^?/? mice. In atherosclerotic plaques of PACAP^?/?/ApoE^?/? mice, the immunoreactive areas of TNF⁺, IL-1β⁺, autophagic, apoptotic and necroptotic cells were increased. In contrast, the overall cell density was decreased compared to ApoE^?/? under SC, while no differences were seen under CED. Similar plasma cholesterol levels were observed in PACAP^?/?/ApoE^?/? and ApoE^?/? mice under the respective feeding regime. Thus, PACAP^?/-/ApoE^?/? mice represent a novel mouse model of accelerated atherosclerosis where CED is not required. Our data indicate that PACAP acts as an endogenous atheroprotective neuropeptide. Thus, stable PACAP agonists may have potential as anti-atherosclerotic therapeutics. The specific PACAP receptor(s) mediating atheroprotection remain(s) to be identified.     

Particulate poly(methyl methacrylate) could stimulate proinflammatory CD4 T cell responses in a monocyte-dependent manner,and directly mediate cell death

Poly(methyl methacrylate) (PMMA) is a synthetic polymer that has been widely used in various medical implants. Traditionally considered a biologically inert material, it is now understood that PMMA may have proinflammatory properties. Here, we present a proof-of-concept study of the effect of PMMA on CD4 T cells. Using particulate PMMA, a material that resembled wear debris in orthopedic implants, to stimulate whole peripheral blood mononuclear cells, we found that the expression of IFNgamma, IL-4, IL-17, and TGFbeta could all be upregulated in CD4 T cells in a manner that was dependent on the dose of particulate PMMA. Furthermore, compared to direct anti-CD3/CD28 stimulation, PMMA preferentially stimulated the expression of IFNgamma and IL-17 but not the expression of IL-4 or TGFbeta. Interestingly, the presence of autologous monocytes was required, since PMMA had no stimulatory effect on isolated CD4 T cells. We further demonstrated that direct monocyte-CD4 T cell contact was required, and the costimulatory molecules CD80 and CD86 were involved for the optimal stimulation of CD4 T cells. PMMA also directly mediated the death of CD4 T cells in a manner that was dependent on dose but independent of the presence of monocytes. Overall, our study revealed that PMMA could induce CD4 T cell death, and also could result in CD4 T cell activation with a preference toward proinflammatory responses in a monocyte-dependent manner.     

Pathogens and autoimmune hepatitis

Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.     

急性冠脉综合征患者住院早期应用不同剂量国产辛伐他汀的临床研究

目的:探讨急性冠脉综合征(ACS)患者住院早期(2天内)应用不同剂量国产辛伐他汀后血清C反应蛋白(CRP)以及血脂的变化及其临床意义。方法:本研究为前瞻性对照研究,连续入选ACS110例患者,随机分为三组:辛伐他汀20 mg组37例、10mg组37例;对照组36例。他汀类两组均于入院24~48 h内给予辛伐他汀治疗。测定三组入院时、入院后4周、8周高敏C反应蛋白(hs-CRP)和血脂的变化。随访近期内(2个月)发生心性事件。结果:(1)ACS住院早期应用辛伐他汀可明显降低炎症因子,且20 mg作用优于10mg。这种益处早在治疗4周后即可见,8周时更为明显。治疗4周后TC、LDL-C开始下降,与治疗前比较差异有显著意义;而且随访期间治疗组的心肌梗死发生率、再住院率均明显低于对照组;(2)ACS患者住院后尽早(24~48 h内)开始积极的降脂治疗有益于降低近期心性事件的发生。结论:ACS患者住院早期(24~48 h)应用辛伐他汀可明显降低血脂、降低炎症因子,可能有利于动脉粥样斑块的稳定,20mg作用明显优于10mg。     

MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression – First results of a cross-sectional study

BackgroundAim of this cross-sectional study was the investigation of associations between different rheumatoid arthritis (RA)-related blood parameters and periodontal condition as well as selected periodontal pathogenic bacteria in RA patients under methotrexate (MTX) immunosuppression.MethodsPeriodontal probing depth (PPD), bleeding on probing (BOP) and clinical attachment loss (CAL) were assessed. Periodontal condition was classified into: no/mild and moderate or severe periodontitis (P). Prevalence of selected periodontal pathogenic bacteria and concentration of matrix metalloproteinase 8 (MMP-8) was assessed from the gingival crevicular fluid (GCF) using PCR and ELISA, respectively. Blood samples were analyzed for the concentration of selected rheumatoid parameters. Statistical analysis: t-test, Mann–Whitney-U-Test, exact Fisher tests or chi square test (p < 0.05).ResultsFifty-six patients (mean age 55.07 years, 34 P, 22 no P) were included. While prevalence of periodontal pathogenic bacteria was higher in P patients, no substantial association of bacteria with blood parameters was found. In periodontal diseased participants, MMP-8 concentration in GCF (6.22 ± 7.01 vs. 15.99 ± 13.49; p < 0.01) and blood (2.60 ± 3.57 vs. 5.52 ± 5.92; p < 0.01) was increased, while no correlation between GCF and blood was found (Spearman's rho: 0.175; p = 0.23). Furthermore, higher blood concentrations of MMP-8 and tissue inhibitor of MMP (TIMP-1) were detected in patients with increased periodontal inflammation (BOP positive, p < 0.01).ConclusionPeriodontal inflammation appears associated to MMP-8 and TIMP-1 in blood. Thereby, clinical interaction between periodontal conditions, periodontal pathogenic bacteria and RA-related cytokines remain unclear.     

Intestinal epithelial barrier functions in ageing

The intestinal epithelial barrier protects the mucosa of the gastrointestinal (GI)-tract and plays a key role in maintaining the host homeostasis. It encompasses several elements that include the intestinal epithelium and biochemical and immunological products, such as the mucus layer, antimicrobial peptides (AMPs) and secretory immunologlobulin A (sIgA). These components are interlinked with the large microbial community inhabiting the gut to form a highly sophisticated biological system that plays an important role on many aspects of human health both locally and systemically. Like any other organ and tissue, the intestinal epithelial barrier is affected by the ageing process. New insights have surfaced showing that critical functions, including intestinal stem cell regeneration and regulation of the intestinal crypt homeostasis, barrier integrity, production of regulatory cytokines, and epithelial innate immunity to pathogenic antigens change across life. Here we review the age-associated changes of the various components of the intestinal epithelial barrier and we highlight the necessity to elucidate further the mechanisms underlying these changes. Expanding our knowledge in this area is a goal of high medical relevance and it will help to define intervention strategies to ameliorate the quality of life of the ever-expanding elderly population.