A novel TLR2‐triggered signalling crosstalk synergistically intensifies TNF‐mediated IL‐6 induction

Toll‐like receptors (TLR) recognize pathogens and trigger the production of vigorous pro‐inflammatory cytokines [such as tumour necrosis factor (TNF)] that induce systemic damages associated with sepsis and chronic inflammation. Cooperation between signals of TLR and TNF receptor has been demonstrated through the participation of TNF receptor 1 (TNFR) adaptors in endotoxin tolerance. Here, we identify a TLR2‐mediated synergy, through a MyD88‐independent crosstalk, which enhances subsequent TNF‐mediated nuclear factor‐kappa B activation and interleukin‐6 induction. Membrane‐associated adaptor MAL conduces the link between TNF receptor‐associated factor 6 (TRAF6) and TNFR‐associated death domain, leading to a distinctive K63‐ubiquitinylated TRAF6 recruitment into TNFR complex. In summary, our results reveal a novel route of TLR signal that synergistically amplifies TNF‐mediated responses, indicating an innovative target for inflammation manipulation.     

A reduced mathematical model of the acute inflammatory response II. Capturing scenarios of repeated endotoxin administration

Bacterial lipopolysaccharide (LPS; endotoxin) is a potent immunostimulant that can induce an acute inflammatory response comparable to a bacterial infection. Experimental observations demonstrate that this biological response can be either blunted (tolerance) or augmented (potentiation) with repeated administration of endotoxin. Both phenomena are of clinical relevance. We show that a four-dimensional differential equation model of this response reproduces many scenarios involving repeated endotoxin administration. In particular, the model can display both tolerance and potentiation from a single parameter set, under different administration scenarios. The key determinants of the outcome of our simulations are the relative time-scales of model components. These findings support the hypothesis that endotoxin tolerance and other related phenomena can be considered as dynamic manifestations of a unified acute inflammatory response, and offer specific predictions related to the dynamics of this response to endotoxin.     

Zingerone Suppresses Liver Inflammation Induced by Antibiotic Mediated Endotoxemia through Down Regulating Hepatic mRNA Expression of Inflammatory Markers in Pseudomonas aeruginosa Peritonitis Mouse Model

Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti-inflammatory phytomedicine against hepatic inflammation induced by antibiotic mediated endotoxemia. These results thus suggest that zingerone treatment can be used as a co-therapy with antibiotics to reduced endotoxin induced inflammation during treatment of severe P.aeruginosa infections.     

New Insights into Cytokine Gene Expression in the Rat Hypothalamus Following Endotoxin Challenge

Peripheral injection of the endotoxin LPS in rats 3 weeks prior to a second injection of LPS derived from another bacterial strain results in elevated corticosterone and decreased pro-inflammatory cytokines in the blood. We further investigated this model by measuring cytokine expression in the hypothalamus and spleen. In LPS-pretreated rats, hypothalamic expression of a range of cytokines was attenuated in response to the second injection of LPS while splenic expression was elevated. This is the first demonstration that prior exposure to an endotoxin can differentially affect cytokine expression in the brain and peripheral tissues when a host is confronted with a second, acute, pro-inflammatory stimulus. Changes in hypothalamic cytokine expression in endotoxin pretreated rats may provide new evidence for the involvement of central cytokine pathways in modulating peripheral inflammation and mediating psychopathological alterations associated with inflammatory diseases.     

Toll样受体与脑缺血

脑缺血是临床上的常见病,目前已成为导致人类死亡的主要原因之一,脑缺血后存在一个十分复杂的病理生理过程,涉及很多机制。包括离子稳态的破坏,自由基的损伤作用,兴奋性氨基酸的毒性作用,免疫炎症作用和细凋亡等机制。TOLL样受体即TLR（Toll-like receptor TLR）,是一类介导天然免疫的跨膜信号传递受体家族,在细胞活化信号传导中发挥着重要作用,已成为联系天然免疫和后天性免疫的桥梁。现在共发现了13中TOLL样体,最近发现Toll样受体能诱发机体的固有免疫应答,介导炎症因子细胞因子的释放,与全身多种重要器官的缺血再灌注损伤有关,研究表明部分TOLL样受体在脑缺血损伤中发挥十分重要的作用。本文就TLR的结构、分布、配体、信号转导通路及其脑缺血中的作用综述如下。     

Toll样受体与脑缺血

脑缺血是临床上的常见病,目前已成为导致人类死亡的主要原因之一,脑缺血后存在一个十分复杂的病理生理过程,涉及很多机制。包括离子稳态的破坏,自由基的损伤作用,兴奋性氨基酸的毒性作用,免疫炎症作用和细凋亡等机制。TOLL样受体即TLR(Toll-like receptor TLR),是一类介导天然免疫的跨膜信号传递受体家族,在细胞活化信号传导中发挥着重要作用,已成为联系天然免疫和后天性免疫的桥梁。现在共发现了13中TOLL样体,最近发现Toll样受体能诱发机体的固有免疫应答,介导炎症因子细胞因子的释放,与全身多种重要器官的缺血再灌注损伤有关,研究表明部分TOLL样受体在脑缺血损伤中发挥十分重要的作用。本文就TLR的结构、分布、配体、信号转导通路及其脑缺血中的作用综述如下。     

Nonmicrobial-mediated inflammatory airway diseases—an update

In lungs, airways are in constant contact with air, microbes, allergens, and environmental pollutants. The airway epithelium represents the first line of lung defense through different mechanisms, which facilitate clearance of inhaled pathogens and environmental particles while minimizing an inflammatory response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage through toll-like receptor, which acts as a gateway for all intracellular events leading to inflammation. In the absence of microbial stimulus, the immune system is capable of detecting a wide range of insults against the host. This review focuses on various molecular mechanisms involved in pathophysiology of airway inflammation mediated by environmental factors, cellular stress, and pharmacological and clinical agents.     

Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells

Classical (M1) and alternative (M2) polarization of mononuclear cells (MNCs) such as monocyte and macrophages is known to occur in response to challenges within a microenvironment, like the encounter of a pathogen. LPS, also known as endotoxin, is a potent inducer of inflammation and M1 polarization. LPS can also generate an effect in MNCs known as endotoxin tolerance, defined as the reduced capacity of a cell to respond to LPS activation after an initial exposure to this stimulus. Using systems biology approaches in PBMCs, monocytes, and monocyte-derived macrophages involving microarrays and advanced bioinformatic analysis, we determined that gene responses during endotoxin tolerance were similar to those found during M2 polarization, featuring gene and protein expression critical for the development of key M2 MNC functions, including reduced production of proinflammatory mediators, expression of genes involved in phagocytosis, as well as tissue remodeling. Moreover, expression of different metallothionein gene isoforms, known for their role in the control of oxidative stress and in immunomodulation, were also found to be consistently upregulated during endotoxin tolerance. These results demonstrate that after an initial inflammatory stimulus, human MNCs undergo an M2 polarization probably to control hyperinflammation and heal the affected tissue.     

A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation

Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting that they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the present study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA to specifically target extracellular pools of cyclophilins. In this study, we show that treatment with this compound in a mouse model of allergic lung inflammation demonstrates up to 80% reduction in inflammation, directly inhibits the recruitment of Ag-specific CD4(+) T cells, and works equally well when delivered at 100-fold lower doses directly to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular functions of cyclophilins may provide an approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, Ag-specific CD4(+) T cells, into inflamed airways and lungs.