The unexpected link between infection-induced apoptosis and a TH17 immune response

Microbial pathogens can initiate MOMP in host cells and as such, initiate the mitochondrial pathway of apoptosis. Innate immune recognition of cells dying in this way by infection-induced apoptosis would involve recognition of ligands derived from the apoptotic host cell simultaneously with those derived from the infecting pathogen. The resultant signal transduction pathways engaged direct DCs to concomitantly synthesize TGF-β and IL-6, two cytokines that subsequently favor the differentiation of na?ve CD4 T cells into T(h)17 cells. Citrobacter rodentium is one rodent pathogen that targets mitochondria and induces apoptosis, and blockade of apoptosis during enteric Citrobacter infection impairs the characteristic T(h)17 response in the intestinal LP. Here, we review these original findings. We discuss microbial infections other than Citrobacter that have been shown to induce T(h)17 responses, and we examine what is known about the ability of those pathogens to induce apoptosis. We also consider types of cell death other than apoptosis that can be triggered by microbial infection, and we highlight how little we know about the impact of various forms of cell death on the ensuing adaptive immune response.     

Stress proteins may provide a link between the immune response to infection and autoimmunity

Stress proteins are frequently the target of humoral and cell-mediatedimmune responses to infection. These proteins belong to highlyconserved gene families and there is substantial sequence homologybetween antigens produced by pathogenic organisms and the correspondingproteins from mammalian cells. Human T cells from sites of infectiousand autoimmune lesions proliferate in response to stress proteins,and mapping of antigenic determinants on a mycobacterial stressprotein shows that both species specific and highly conserved,‘self-like’, regions of the molecule can take partin immune recognition. It is proposed that the lymphocyte populationinduced in response to stress proteins of pathogens during infectionincludes cells capable of autolmmune recognition of the correspondingself protein. Local accumulation of self stress proteins—inresponse to viral infection, for example—may subsequentlyprovide a stimulus for proliferation of such autoreactive lymphocytes,thereby triggering a cycle of events which may contribute tothe pathological damage associated with autoimmune disease.     

ERK和P38MAPK升高MLC20磷酸化调节大鼠平滑肌低氧反应性

目的 研究丝裂原活化蛋白激酶(MAPK)亚类ERK、P38 MAPK和JNK在低氧血管平滑肌收缩反应性调节中的作用,并从肌球蛋白轻链(MLC20)磷酸化的钙敏感性调节途径上初步探讨其机制.方法 用低氧培养血管平滑肌细胞(VSMC)模型和大鼠失血性休克模型,用荧光法检测VSMC收缩反应,用Western blot检测血管...     

IFN-alpha and IFN-beta: a link between immune memory and chronic inflammation

The majority of expanded T cells generated during an immune response are cleared by apoptosis. Prevention of death in some activated T cells enables the persistence of a memory T-cell pool. Here, observations that IFN-alpha and IFN-beta inhibit activated T-cell apoptosis are described. Although this enables memory T cells to persist without antigen, excessive IFN-alpha or IFN-gamma secretion might lead to chronic inflammation.     

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy.     

Cyclooxygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition

Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in vivo data on the cause of this inhibition are scarce, in vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasma-cell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs.     

Signaling pathways involved in the physiological response of mussel hemocytes to bacterial challenge: the role of stress-activated p38 MAP kinases

In this work the mechanisms of transduction triggered in Mytilus galloprovincialis hemocytes by bacterial challenge were investigated in an in vitro model of infection of hemocyte monolayers with Escherichia coli. Western blot analyses of hemocyte extracts with phospho-specific anti-MAPK (Mitogen Activated Protein Kinase) antibodies indicate that E. coli induced a time dependent activation of different classes of MAPKs, mainly of the stress-activated p38 MAPK. P38 activation was confirmed by the use of the selective kinase inhibitor SB203580. Moreover, hemocyte pretreatment with SB203580 significantly reduced bacterial killing, whereas PD98059, an inhibitor of extracellularly regulated kinase (ERK) activation, was ineffective. Interestingly, the PI3-kinase (phosphatidylinositol-3-OH-kinase) inhibitor, Wortmannin, reduced both p38 activation and bacterial killing, indicating a critical role also for this lipid kinase in the hemocyte immune response.     

The importance of beta-adrenergic receptors in immune regulation: a link between neuroendocrine and immune system

Our knowledge of autoimmunity and autoimmune diseases has been advanced in the past decades. Receptors present on the immune cells may potentially regulate the immune system, among them, beta-adrenergic receptors are of special interest. As neurotransmitter receptors which are also present on lymphocytes, beta-adrenergic receptors play an important role as the linkage of two important systems, neuroendocrine and immune systems. Here I summarize several lines of evidence of the importance of the beta-adrenergic receptors in immune regulation.     

The potential pathogenetic link between peripheral immune activation and the central innate immune response in neuropsychiatric systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Neuropsychiatric disturbances unexplained by drugs or by other untoward manifestations of disease are present in up to one-half of SLE patients and have profound economic and social impact. In patients with neuropsychiatric SLE, structural lesions have been identified in the hippocampus and proinflammatory cytokines have been detected in the cerebrospinal fluid. Similarly, murine models of lupus, such as MRL-lpr/lpr mice display behavioral disturbances which map to the hippocampus and exhibit overexpression of proinflammatory cytokine genes in hippocampal homogenates. Neuropsychiatric SLE typically occurs in the presence of serologically and clinically active lupus. In animal models of SLE, such as MRL-lpr/lpr, NZB, BXSB, and [NZB x NZW]F(1), uncontrolled autoreactivity in the periphery is accompanied by behavioral disturbances that are chronic and progressive. These observations suggest the hypothesis that central nervous system disease in SLE is driven by cross-talk between the peripheral immune system and the brain's innate immune system, which results in the inexorable activation of astrocytes, microglia, and/or neurons within the hippocampus. This leads to overproduction of brain cytokines, which induce the synthesis of pro-oxidant molecules, such as eicosanoids and reactive oxygen species, with resultant tissue injury. The cascade becomes self-perpetuating and eventuates in neuronal death, which is followed by impaired cognition. A better understanding of the molecular events that operate in the pathogenesis of neuropsychiatric SLE may provide the basis for a more rational therapeutic approach to this incompletely understood disease.     

Viruses and the fuel sensor: the emerging link between AMPK and virus replication

Adenosine 5′ monophosphate‐activated protein kinase (AMPK) is conserved in all eukaryotic cells and functions as the key regulator of cellular metabolism by responding to the energy status of the cell. It is activated by an increase in the AMP : ATP ratio and then attempts to redress the balance by upregulating catabolic processes, whilst concomitantly inhibiting anabolic processes. Despite its critical importance in the functioning of eukaryotic cells, there has been a paucity of studies investigating the potential for dysregulation of AMPK by viruses. Recently, however, there have been a number of reports that have begun to address this gap in our knowledge. In this article, we will review this emerging field, outlining how a variety of viruses have been shown to either stimulate or inhibit AMPK activity. We will also document the effects of these perturbations on the biology of virus infection, in particular with regard to the ability of viruses to persist or cause cytopathogenesis. Copyright © 2011 John Wiley & Sons, Ltd.     

Dectin-1 on macrophages modulates the immune response to Fasciola hepatica products through the ERK signaling pathway

Fasciolosis is a zoonotic disease of increasing importance due to its worldwide distribution and elevated economic losses. Previously, we demonstrated that Fasciola hepatica excretory–secretory products (FhESP) induce immunomodulatory effects on peritoneal macrophages in a Dectin-1 dependent manner.In this study, we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented increased expression levels of phosphorylated extracellular-signal-regulated kinase (ERK), and this effect was dependent on Syk, protein kinase C (PKC) and Dectin-1. In this sense, we observed increased levels of arginase activity, IL-10 and TGF-β in macrophages stimulated with FhESP, which were dependent on PKC and ERK. Furthermore, we observed that the increased arginase activity, as well as in TGF-β and IL-10 levels, was partially dependent on IL-10 receptor signaling in macrophages that were pre-incubated with anti-IL10R before being stimulated with FhESP.Taken together, these results suggest the participation of Dectin-1 and Syk in FhESP interaction with peritoneal macrophages and the possible role of ERK and IL-10 in downstream signaling pathways involved in the immunomodulatory effects induced by Fasciola hepatica products.     

Prolactin as a link between behavioral and immune differences between the Roman rat lines.

Roman high (RHA)- and low (RLA)-avoidance rats are two lines of Wistar rats genetically selected on the basis of their active avoidance behavior in a shuttle-box. They also differ in several other behavioral responses, such as their locomotor activity in novel environments (open-field, circular corridor), with the RHA rats being more active than the RLA animals, as well as in endocrine reactivity and immune functions. These experiments were designed to investigate further the neuroendocrine characteristics of these animals as a possible link between the brain and immune functions. Despite the marked behavioral and immune differences observed, no between-lines variation could be found in basal hypothalamo-pituitary-adrenocortical axis activity or in its responses to different protocols of novel environment stress, or after corticotropin-releasing factor (CRF) challenge. On the other hand, stimulated prolactin levels were higher in the low avoidance line. These results exclude the pituitary-adrenocortical axis and suggest prolactin as a link between behavioral and immune differences between the Roman lines. Moreover, these results indicate that these rats may be an excellent model for the study of the relationships between the brain and the immune system.     

The p38 pathway is activated in Pick disease and progressive supranuclear palsy: a mechanistic link between mitogenic pathways,oxidative stress,and tau

In Pick disease and progressive supranuclear palsy (PSP), accumulations of phosphorylated tau are associated with oxidative stress, although the mechanism linking these features remains unknown. However, we suspected that the oxidative stress-induced activation of mitogen-activated protein kinases might lead to tau phosphorylation and accumulation as characteristic inclusion bodies. To test this notion, we investigated whether the activation of mitogen-activated protein kinases is involved in the pathogenesis of Pick disease and PSP. Our results show that the lesions of both Pick disease and PSP are associated with the activation of the p38 pathway (phospho-MKK6 and phospho-p38), one of the best characterized of the mitogen-activated protein kinase pathways. Based on these findings, we propose that the phosphorylation of tau is a direct consequence of the oxidative stress-induced activation of mitogen-activated protein kinases, including p38.     

藏红花素通过KCa3.1及ERK调节HUVECs增殖、迁移过程

目的 观察藏红花素对人脐静脉内皮细胞(HUVECs)增殖、迁移的影响以及中电导钙激活钾通道(KCa3.1)可能的调节作用.方法 用藏红花素及ERK激酶(MEK)抑制剂PD98059、KCa3.1抑制剂TRAM-34 处理 HUVECs,MTT和EdU细胞增殖法检测细胞体外增殖活力,Transwell评估细胞迁移能力,W...     

Short chain fatty acids may elicit an innate immune response from preadipocytes: a potential link between bacterial infection and inflammatory diseases

Short chain fatty acids (SCFAs) such as acetate, propionate and butyrate are produced by bacterial fermentation of dietary fiber. The highest concentrations of SCFAs in the body are found in the colon. Elevated dietary acetate has been shown to have anti-inflammatory effects in mouse models of colitis and inflammatory diseases in peripheral tissues. The details of how dietary SCFAs stimulate reduced inflammation in peripheral tissues have not been determined. I suggest that SCFA concentrations in peripheral tissues are generally not sufficient to locally produce a significant anti-inflammatory effect from immune cells. Moreover it is possible that elevated SCFA levels in peripheral tissues may actually stimulate an inflammatory response. The hypothesis is presented that preadipocytes and other cells with immune function such as fibroblasts in peripheral tissues elicit an inflammatory innate immune response when exposed to SCFAs at millimolar concentrations. A role for SCFAs in activating an immune response in preadipocytes is possible given the expression of a SCFA receptor in these cells, the demonstration that adipocytes and preadipocytes have immunity related functions, the observation that 2mM SCFAs stimulated the expression of monocyte chemoattractant protein-1 (MCP-1) mRNA from 3T3-L1 preadipocytes and that concentrations of SCFAs can reach elevated levels at sites of bacterial infection. A SCFA-induced inflammatory response from preadipocytes and other cells with immune function, such as fibroblasts, may provide a further contributing factor linking bacterial infection to the development of insulin resistance and the severity of inflammatory diseases such as atherosclerosis.     

LIM Mineralization Protein-1 Enhances the Committed Differentiation of Dental Pulp Stem Cells through the ERK1/2 and p38 MAPK Pathways and BMP Signaling

Tissue regeneration is the preferred treatment for dentin and bone tissue defects. Dental pulp stem cells (DPSCs) have been extensively studied for their use in tissue regeneration, including the regeneration of dentin and bone tissue. LIM mineralization protein-1 (LMP-1) is an intracellular non-secretory protein that plays a positive regulatory role in the mineralization process. In this study, an LMP-1-induced DPSCs model was used to explore the effect of LMP-1 on the proliferation and odonto/osteogenic differentiation of DPSCs, as well as the underlying mechanisms. As indicated by the cell counting kit-8 assay, the results showed that LMP-1 did not affect the proliferation of DPSCs. Overexpression of LMP-1 significantly promoted the committed differentiation of DPSCs and vice versa, as shown by alkaline phosphatase activity assay, alizarin red staining, western blot assay, quantitative real-time polymerase chain reaction assay, and in vivo mineralized tissue formation assay. Furthermore, inhibiting the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways using specific pathway inhibitors showed that the ERK1/2 and p38 MAPK pathways attenuated the differentiation of DPSCs. Besides, the expression of BMP signaling pathway components were also determined, which suggested that LMP-1 could activate BMP-2/Smad1/5 signaling pathway. Our results not only indicated the underlying mechanism of LMP-1 treated DPSCs but also provided valuable insight into therapeutic strategies in regenerative medicine.     

Potential link between the immune system and metabolism of nucleic acids

During microbial infection and tissue injury, nucleic acids and their metabolites, such as nucleotides, nucleosides and uric acids, can be released from dying host cells and may modify immune responses. These nucleic acids and/or their metabolites are in fact recognized by specific host receptors, such as Toll-like receptors (TLRs), RIG-like receptors (RLRs) and NOD-like receptors (NLRs), purinergic receptors such as P2X and P2Y receptors, and adenosine receptors such as A2A receptors. The resultant responses may vary depending on the balance between immune responses to and metabolism of nucleic acids, thereby contributing not only to the host defense, but also to the homeostatic clearance of host dying cells, or even to deleterious autoimmune diseases.