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At least 1,639 records · Page 91Linked to original sources
PubMed2006

Identification of a TLR-independent pathway for Borrelia burgdorferi-induced expression of matrix metalloproteinases and inflammatory mediators through binding to integrin alpha 3 beta 1.

Borrelia burgdorferi stimulates a robust inflammatory response at sites of localization. Binding of borrelial lipoproteins to TLR-2 is one pathway important in the host response to B. burgdorferi. However, while TLR-2 is clearly important in control of infection, inflammation is actually worsened in the absence of TLR-2 or the shared TLR adapter molecule, MyD88, suggesting that there are alternative pathways regulating inflammation. Integrins are cell surface receptors that play an important role in cell to cell communications and that can activate inflammatory signaling pathways. In this study, we report for the first time that B. burgdorferi binds to integrin alpha(3)beta(1) and that binding of B. burgdorferi to this integrin results in induction of proinflammatory cytokines, chemokines, and end-effector molecules such as matrix metalloproteinases in primary human chondrocyte cells. Expression of these same molecules is not affected by the absence of MyD88 in murine articular cartilage, suggesting that the two pathways act independently in activating host inflammatory responses to B. burgdorferi. B. burgdorferi-induced alpha(3) signaling is mediated by JNK, but not p38 MAPK. In summary, we have identified a new host receptor for B. burgdorferi, integrin alpha(3)beta(1); binding of B. burgdorferi to integrin alpha(3)beta(1) results in the release of inflammatory mediators and is proposed as a TLR-independent pathway for activation of the innate immune response by the organism.

Adaptor Proteins, Signal Transducing↗
PubMed2006

TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus.

The nucleosome is a major autoantigen in systemic lupus erythematosus (SLE); it can be detected as a circulating complex in the serum, and nucleosomes have been suggested to play a key role in disease development. In the present study, we show for the first time that physiological concentrations of purified nucleosomes trigger innate immunity. The nucleosomes are endocytosed and induce the direct activation of human neutrophils (polymorphonuclear leukocytes (PMN)) as revealed by CD11b/CD66b up-regulation, IL-8 secretion, and increased phagocytic activity. IL-8 is a neutrophil chemoattractant detected in high concentrations in the sera of patients, and IL-8 secretion might thus result in enhanced inflammation, as observed in lupus patients, via an amplification loop. Nucleosomes act as free complexes requiring no immune complex formation and independently of the presence of unmethylated CpG DNA motifs. Both normal and lupus neutrophils are sensitive to nucleosome-induced activation, and activation is not due to endotoxin or high-mobility group box 1 contamination. In mice, i.p. injection of purified nucleosomes induces neutrophil activation and recruitment in a TLR2/TLR4-independent manner. Importantly, neutrophils have been suggested to link innate and adaptive immunity. Thus, nucleosomes trigger a previously unknown pathway of innate immunity, which may partially explain why peripheral tolerance is broken in SLE patients.

Animals↗
PubMed2006

CpG DNA activates survival in murine macrophages through TLR9 and the phosphatidylinositol 3-kinase-Akt pathway.

Bacterial CpG-containing (CpG) DNA promotes survival of murine macrophages and triggers production of proinflammatory mediators. The CpG DNA-induced inflammatory response is mediated via TLR9, whereas a recent study reported that activation of the Akt prosurvival pathway occurs via DNA-dependent protein kinase (DNA-PK) and independently of TLR9. We show, in this study, that Akt activation and survival of murine bone marrow-derived macrophages (BMM) triggered by CpG-containing phosphodiester oligodeoxynucleotides or CpG-containing phosphorothioate oligodeoxynucleotides was completely dependent on TLR9. In addition, survival triggered by CpG-containing phosphodiester oligodeoxynucleotides was not compromised in BMM from SCID mice that express a catalytically inactive form of DNA-PK. CpG DNA-induced survival of BMM was inhibited by the PI3K inhibitor, LY294002, but not by the MEK1/2 inhibitor, PD98059. The effect of LY294002 was specific to survival, because treatment of BMM with LY294002 affected CpG DNA-induced TNF-alpha production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.

Animals↗
PubMed2006

The role of human antigen R, an RNA-binding protein, in mediating the stabilization of toll-like receptor 4 mRNA induced by endotoxin: a novel mechanism involved in vascular inflammation.

OBJECTIVE: Lipopolysaccharide (LPS) interacts with toll-like receptor 4 (TLR4) and induces proliferation of vascular smooth muscle cells (VSMCs) which plays a causal role in atherogenesis. The role of TLR4 expression and regulation in LPS-stimulated VSMCs remains unclear. TLR4 mRNAs often contain AU-rich elements (AREs) in their 3' untranslated regions (3'UTR) which have a high affinity for RNA-binding proteins. It is not know whether the RNA-binding protein, human antigen R (HuR), regulates TLR4 expression in human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: Stimulation of HASMCs with LPS significantly increased the cytosolic HuR level in vitro. Immunoprecipitation and RT-PCR demonstrated that LPS markedly increased the interaction of HuR and 3'UTR of TLR4 mRNA. The reporter plasmid, which contains the 3'UTR of TLR4 mRNA, significantly increased luciferase reporter gene expression in LPS-induced HASMCs. These data suggest that the 3'UTR of TLR4 mRNA confers LPS responsiveness and that HuR modulates 3'UTR-mediated gene expression. Knock-down of HuR inhibited LPS-induced TLR4 mRNA stability in HASMCs and luciferase reporter gene expression in CMV-Luciferase-TLR4 3'UTR-transfected HASMCs. In addition, inhibition of NADPH oxidase activity by diphenylene iodonium, knock-down of Rac1 gene expression by siRNA, and decrease of p38 MAPK activity by SB203580 significantly decreased the cytosolic HuR level, which mediates TLR4 mRNA stability. CONCLUSIONS: Activation of NADPH oxidase and the MAPK-signaling pathway contribute to HuR-mediated stabilization of TLR4 mRNA induced by LPS in HASMCs. In the balloon injured rabbit aorta model, systemic inflammation induced by LPS caused intimal hyperplasia and increased TLR4 and HuR expression.

Animals↗
PubMed2001

Novel NEMO/IkappaB kinase and NF-kappa B target genes at the pre-B to immature B cell transition.

The IkappaB kinase (IKK) signaling complex is responsible for activating NF-kappaB-dependent gene expression programs. Even though NF-kappaB-responsive genes are known to orchestrate stress-like responses, critical gaps in our knowledge remain about the global effects of NF-kappaB activation on cellular physiology. DNA microarrays were used to compare gene expression programs in a model system of 70Z/3 murine pre-B cells versus their IKK signaling-defective 1.3E2 variant with lipopolysaccharide (LPS), interleukin-1 (IL-1), or a combination of LPS + phorbol 12-myristate 13-acetate under brief (2 h) or long term (12 h) stimulation. 70Z/3-1.3E2 cells lack expression of NEMO/IKKgamma/IKKAP-1/FIP-3, an essential positive effector of the IKK complex. Some stimulated hits were known NF-kappaB target genes, but remarkably, the vast majority of the up-modulated genes and an unexpected class of repressed genes were all novel targets of this signaling pathway, encoding transcription factors, receptors, extracellular ligands, and intracellular signaling factors. Thirteen stimulated (B-ATF, Pim-2, MyD118, Pea-15/MAT1, CD82, CD40L, Wnt10a, Notch 1, R-ras, Rgs-16, PAC-1, ISG15, and CD36) and five repressed (CCR2, VpreB, lambda5, SLPI, and CMAP/Cystatin7) genes, respectively, were bona fide NF-kappaB targets by virtue of their response to a transdominant IkappaBalphaSR (super repressor). MyD118 and ISG15, although directly induced by LPS stimulation, were unaffected by IL-1, revealing the existence of direct NF-kappaB target genes, which are not co-induced by the LPS and IL-1 Toll-like receptors.

Animals↗
PubMed2004

Induction and regulation of IFNs during viral infections.

Interferons (IFN)s are involved in numerous immune interactions during viral infections and contribute to both induction and regulation of innate and adaptive antiviral mechanisms. IFNs play a pivotal rule in the outcome of a viral infection, as demonstrated by the impaired resistance against different viruses in mice deficient for the receptors IFNAR-2 and IFNGR. During viral infections, IFNs are involved in numerous immune interactions as inducers, regulators, and effectors of both innate and adaptive antiviral mechanisms. IFN-alpha/beta is produced rapidly when viral factors, such as envelope glycoproteins, CpG DNA, or dsRNA, interact with cellular pattern-recognition receptors (PRRs), such as mannose receptors, toll-like receptors (TLRs), and cytosolic receptors. These host-virus interactions signal downstream to activate transcription factors needed to achieve expression from IFN-alpha/beta genes. These include IFN regulatory factor-3 (IRF-3), IRF-5, IRF-7, c-Jun/ATF-2, and NF-kappaB. In contrast, IFN-gamma is induced by receptor-mediated stimulation or in response to early produced cytokines, including interleukin-2 (IL-12), IL-18, and IFN-alpha/beta, or by stimulation through T cell receptors (TCRs) or natural killer (NK) cell receptors. IFNs signal through transmembrane receptors, activating mainly Jak-Stat pathways but also other signal transduction pathways. Cytokine and TCR-induced IFN-gamma expression uses distinct signal transduction pathways involving such transcription factors as NFAT, Stats and NF-kappaB. This results in induction and activation of numerous intrinsic antiviral factors, such as RNA-activated protein kinase (PKR), the 2-5A system, Mx proteins, and several apoptotic pathways. In addition, IFNs modulate distinct aspects of both innate and adaptive immunity. Thus, IFN-alpha/beta and IFN-gamma affect activities of macrophages, NK cells, dendritic cells (DC), and T cells by enhancing antigen presentation, cell trafficking, and cell differentiation and expression profiles, ultimately resulting in enhanced antiviral effector functions. This review focuses on the latest findings regarding induction and regulation of IFNs, primarily during the early phase of an antiviral immune response. Both cellular and molecular aspects are discussed from the perspective of host-virus interactions.

Animals↗
PubMed2006

Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury.

The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-alpha and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-kappaB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway.

Animals↗
PubMedDate not supplied

Genetic variation associated with preterm birth: a HuGE review.

Preterm birth (PTB) is a major public health concern because of its high prevalence, associated mortality and morbidity, and expense from both short-term hospitalization and long-term disability. In 2002, 11.9% of U.S. births occurred before 37 weeks gestation. Epidemiologic studies have identified many demographic, behavioral, and medical characteristics associated with PTB risk. In addition, recent evidence indicates a role for genetic susceptibility. We reviewed 18 studies published before June 1, 2004, that examined associations between polymorphisms in the maternal or fetal genome and PTB risk. Studies of a polymorphism in tumor necrosis factor-alpha, a proinflammatory cytokine, showed the most consistent increase in the risk of PTB. Environmental factors such as infection, stress, and obesity, which activate inflammatory pathways, have been associated with PTB, suggesting that environmental and genetic risk factors might operate and interact through related pathways. This review highlights maternal and fetal genetic susceptibilities to PTB, the potential relationships with environmental risk factors, and the need for additional well-designed studies of this critical public health problem.

Environmental Exposure↗
PubMed2005

Stimulus specificity of gene expression programs determined by temporal control of IKK activity.

A small number of mammalian signaling pathways mediate a myriad of distinct physiological responses to diverse cellular stimuli. Temporal control of the signaling module that contains IkappaB kinase (IKK), its substrate inhibitor of NF-kappaB (IkappaB), and the key inflammatory transcription factor NF-kappaB can allow for selective gene activation. We have demonstrated that different inflammatory stimuli induce distinct IKK profiles, and we examined the underlying molecular mechanisms. Although tumor necrosis factor-alpha (TNFalpha)-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide (LPS) signaling and LPS-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, the distinct biological responses to LPS and TNFalpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.

Algorithms↗
PubMed2005

Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways.

Exposure of the mammalian host to infective larvae of Schistosoma mansoni causes an acute inflammatory response in the skin and the activation of several cell types of the innate immune response including macrophages. Using an in vitro model of macrophage activation, we show that schistosome larvae possess molecules that directly stimulate both thioglycollate-elicited macrophages (tM) and IFNgamma-activated tM in vitro to produce several cytokines including IL-6, IL-12p40 and IL-10. The parasite-derived molecules are enriched within the material released by the parasite following transformation [0- to 3-h released larval preparation (0-3hRP)] but not within soluble preparations of whole larvae. Cytokine production was maintained in the presence of polymyxin B, confirming that contaminating endotoxin was not responsible. IL-12p40 and IL-10 production was much lower by cells from C3H/HeJ mice, which have defective Toll-like receptor 4 (TLR4), but IL-6 production was unaffected. Experiments using TLR4-/- mice confirmed that IL-12p40 production by tM in response to 0-3hRP was partly dependent upon functional TLR4, whereas IL-6 production was entirely independent. In contrast, tM from MyD88-/- mice failed to secrete either IL-12p40 or IL-6, underlining a pivotal role of TLR signalling in cytokine production by macrophages in response to stimulation with 0-3hRP. Finally, we show that glycan components of 0-3hRP are required for optimal cytokine production since protease treatment of 0-3hRP had no effect on IL-12p40 production and only a slight effect on IL-6, while sodium meta-periodate treatment almost completely abolished production of both cytokines.

Animals↗
PubMed2005

Human immunodeficiencies that predispose to intracellular bacterial infections.

PURPOSE OF REVIEW: Patients treated with anti-tumour necrosis factor agents have an increased risk of active tuberculosis. Mycobacteria are bacterial pathogens capable of surviving and multiplying within macrophages; these infections are characterised by granulomatous inflammation. This review addresses the effects of inherited and acquired immunodeficiencies on the susceptibility to the development of intracellular bacterial infections. RECENT FINDINGS: Primary and secondary immunodeficiencies that result in severely impaired T cell function or macrophage activation result in an increased risk of mycobacterial and Salmonella infection. Conversely, inherited or acquired antibody or complement deficiency does not lead to increased susceptibility to these pathogens. Inherited defects in the interleukin-12/interleukin-23-dependent interferon-gamma pathway due to mutations in genes encoding the p40 chain common to interleukin-12 and interleukin-23, the beta1 chain shared by interleukin-12 and interleukin-23 receptors, interferon-gamma receptor chains 1 or 2, or signal transducer and activator of transcription, predispose to severe infections caused by poorly pathogenic mycobacteria and Salmonella species. Acquired defects of cytokine function causing increased susceptibility to these pathogens include anti-tumor necrosis factor therapy and the generation of interferon-gamma-neutralising autoantibodies. Defective nuclear factor kappaB activation caused by hypomorphic mutations of the nuclear factor kappaB essential modulator gene, which compromises the function of Toll receptors, interleukin-IL receptors, and tumor necrosis factor-alpha receptors, also increases susceptibility to severe mycobacterial infections. Patients with inherited defects in the phagocyte nicotine-adenine dinucleotide phosphate oxidase system are highly susceptible to Salmonella infections but only exhibit slightly increased susceptibility to mycobacteria. SUMMARY: Collectively, these observations highlight immune mechanisms that are essential for protection against intracellular bacteria. This information provides clinicians with a framework for investigating patients with potentially life-threatening intracellular bacterial infections.

Disease Susceptibility↗
PubMed2004

Regulation of the lipopolysaccharide signal transduction pathway by 17beta-estradiol in macrophage cells.

We have previously shown that 17beta-estradiol (E2) prevents the activation of brain macrophages, i.e. microglia cells, both in vitro and in vivo. Hormone exerts this inhibitory effect by inhibiting pro-inflammatory gene expression. In this study we further investigated on the molecular mechanism of E2 action in the RAW 264.7 macrophage cell line. We show here that these cells express the alpha-isoform of the estrogen receptor (ERalpha) and not ERbeta. Similarly to its activity in brain macrophages, E2 is able to inhibit the activation program induced by lipopolysaccharide (LPS) in RAW 264.7 cells, as shown by the inhibitory effect of hormone on the morphological conversion and matrix metalloproteinase-9 (MMP-9) expression induced by the endotoxin. In addition, we demonstrate that hormone treatment is not associated with a reduction in the steady-state expression of Toll-like receptor-4 (TLR-4) and CD14, two components of the LPS receptor complex. Our results further confirm the anti-inflammatory role of ERalpha in macrophages and propose that the mechanism of hormone action on macrophage reactivity involves signaling molecules which are down-stream effectors of the LPS membrane receptors.

Animals↗
PubMed2000

Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88.

The innate immune system evolved to recognize conserved microbial products, termed pathogen-associated molecular patterns (PAMPs), which are invariant among diverse groups of microorganisms. PAMPs are recognized by a set of germ-line encoded pattern recognition receptors (PRRs). Among the best characterized PAMPs are bacterial lipopolysaccharide (LPS), peptidoglycan (PGN), mannans, and other constituents of bacterial and fungal cell walls, as well as bacterial DNA. Recognition of bacterial DNA is the most enigmatic of these, as it depends on a particular sequence motif, called the CpG motif, in which an unmethylated CpG present in a particular sequence context accounts for a potent immunostimulatory activity of CpG DNA. Receptor(s) of the innate immune system that mediate recognition of CpG DNA are currently unknown. Here, we report that recognition of CpG DNA requires MyD88, an adaptor protein involved in signal transduction by the Toll-like receptors (TLRs), essential components of innate immune recognition in both Drosophila and mammals [1,2]. Signaling induced by CpG DNA was found to be unaffected in cells deficient in TLR2 or TLR4, suggesting that some other member of the Toll family mediates recognition of bacterial DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The kinase complex responsible for IRF-3-mediated IFN-beta production in myeloid dendritic cells (mDC).

Type I interferons (IFN) IFN-alpha and -beta play a central role in the induction of antiviral immunity, which involves up-regulation or activation of a large number of IFN-inducible genes in host immune competent cells. Initial events in the antiviral response may occur in myeloid dendritic cells (mDCs), and the proteins expressed provoke early responses to cope with concomitant infection in the host. The participation of transcription factors IRF-3/7, AP1 and NF-kappaB in IFN-beta promoter activation in mDCs is well established. An initial trigger of this event is a viral dsRNA that is recognized by proteins with an RNA-binding motif. Toll-like receptor (TLR) 3 on membranes and RIG-Iin the cytoplasm are molecules with dsRNA-recognition ability. Our main aim in the present review is to describe how IRF-3 and/or NF-kappaB are activated through the initial recognition of dsRNA by these pattern-recognition receptors. By analogy to the trimolecular complex of IKKgamma, IKKalpha and IKKbeta, thus far, IRF-3-activated kinases have been reported to be kinase complexes with trimolecular assembly. Two kinases, TBK1 and IKKepsilon, are thought to be linked to regulatory subunit TANK or NAP1 with no kinase activity like IKKgamma. The TLR3 and RIG-I pathways converge upstream of IRF-3, possibly at NAP1, the regulatory subunit of IRF-3-activating kinase. Thus, a novel function of the regulatory subunit has emerged. These proteins are involved in the TLR3 and RIG-I pathways, and act as adapters bridging on the dsRNA-recognition unit and IRF-3-activating kinases in addition to their kinase-regulatory function. Here, we summarize the properties of regulatory subunits NAP1 and TANK, and the mode of activation of NF-kappaB and IRF-3 in conjunction with the unique properties of the TLR3 function.

Animals↗
PubMed2006

Screening for Toxoplasma gondii-regulated transcriptional responses in lipopolysaccharide-activated macrophages.

Toxoplasma gondii-infected macrophages are blocked in production of the proinflammatory cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) upon activation with lipopolysaccharide (LPS). Here, we used pathway-focused cDNA arrays to identify additional T. gondii-regulated transcriptional responses. Parasite infection decreased 57 (inclusive of IL-12 and TNF-alpha) and increased expression of 7 of 77 LPS-activated cytokine and cytokine-related genes. Interestingly, we found that the LPS-induced transcriptional response of the anti-inflammatory cytokine IL-10 was synergistically increased by T. gondii, results that we validated by conventional reverse transcription-PCR and enzyme-linked immunosorbent assay. Importantly, although the parasite exerted disparate effects in LPS-signaling leading to TNF-alpha versus IL-10 production, both responses required functional Toll-like receptor 4. We suggest that these effects represent parasite defense mechanisms to avoid or delay induction of antimicrobial activity and/or T-cell-mediated immunity during Toxoplasma infection.

Animals↗
PubMed1995

Endothelium-derived relaxing factors and converting enzyme inhibition.

Endothelial cells can produce at least 3 substances which cause relaxation of vascular smooth muscle: (1) endothelium-derived nitric oxide (NO, which is secreted not only toward the underlying vascular smooth muscle but also into the blood vessel lumen). NO also has a physiological role at the interface between the endothelial cells and the blood content; in particular, NO inhibits the adhesion of platelets and leukocytes to the endothelium. (2) Endothelium-derived hyperpolarizing factor, presumably a labile metabolite of arachidonic acid formed through the P-450 pathway, which appears to act on smooth muscle by being one of the few physiologic openers of the potassium channels. (3) Prostacyclin, which can be considered as an endothelium-derived relaxing substance, given its vasodilator activity and its primarily endothelial origin. One of the main factors modulating the release of these EDRFs is the shear stress of blood on the arterial wall, which explains why flow-induced vasodilation is endothelium-dependent in the intact organism. The peptide bradykinin is a potent stimulus for EDRF release. The normal lifespan of an adult human endothelial cell is some 30 years, after which aging takes its toll and the cells must be replaced. The regenerated cells lose some of their ability to release EDRF, in particular in response to platelet aggregation and thrombin. Finally, in hypertension and atherosclerosis, a decrease in endothelium-dependent relaxation is obvious in response to a variety of stimuli. All converting enzyme inhibitors tested so far share a potentiating effect on endothelium-dependent relaxation to bradykinin, and augmented local production of bradykinin may help to explain the acute vasodilator properties of these compounds.

Adult↗
PubMed2003

Helicobacter pylori induces RANTES through activation of NF-kappa B.

Helicobacter pylori-infected gastric mucosa displays a conspicuous infiltration of mononuclear cells and neutrophils. RANTES (short for "regulated upon activation, normal T cell expressed and secreted") is a chemoattractant cytokine (chemokine) important in the infiltration of T lymphocytes and monocytes. RANTES may therefore contribute to the cellular infiltrate in the H. pylori-infected gastric mucosa. The aim of this study was to analyze the molecular mechanism responsible for H. pylori-mediated RANTES expression. We observed that gastric epithelial cells produced RANTES upon coculture with H. pylori. In addition, H. pylori induced RANTES mRNA expression and an increase in luciferase activity in cells which were transfected with a luciferase reporter construct derived from the RANTES promoter, in gastric epithelial cells, indicating that the induction of RANTES production occurred at the transcriptional level. Induction of RANTES was dependent on an intact cag pathogenicity island. Activation of the RANTES promoter by H. pylori occurred through the action of NF-kappa B. Transfection of kinase-deficient mutants of I kappa B kinase (IKK) and NF-kappa B-inducing kinase (NIK) inhibited H. pylori-mediated RANTES activation. In contrast, tumor necrosis factor alpha- or interleukin-1/Toll-like receptor signaling molecules-such as mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1, MyD88, and interleukin-1 receptor-associated kinase-did not play a role in RANTES activation by H. pylori. Collectively, H. pylori induced NF-kappa B activation through an intracellular signaling pathway that involved IKK and NIK, leading to RANTES gene transcription. RANTES induction by H. pylori may play an important role in gastric inflammation.

Antineoplastic Agents↗
PubMed2006

TLR7 ligands induce higher IFN-alpha production in females.

IFN-alpha exercises multiple immune modulatory and antiviral activities and has been suggested to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) release IFN-alpha upon TLR7 and TLR9 ligation. With respect to the nine times higher incidence of SLE in women and the clinical use of synthetic TLR ligands as novel immune adjuvants, we analyzed IFN-alpha and TNF-alpha production in healthy human individuals. Blood samples were incubated with synthetic TLR7 and TLR9 ligands. In three independent groups (n(1) = 120, n(2) = 101, and n(3) = 123), analysis revealed a capacity of female PBLs to produce significantly higher IFN-alpha levels after TLR7 stimulation (p(1) < 0.0000001, p(2) < 0.0000001, and p(3) < 0.0001) compared with male PBLs. In contrast, no sex differences were evident after TLR9 stimulation. TNF-alpha production after TLR7 stimulation and also total pDC numbers were not different between females and males. X-inactivation escape of the TLR7 gene was investigated in monoclonal B cell lines and, independently, in pDCs after cell sorting and single-cell picking, indicating regular silencing of one TLR7 allele in females. Additionally, exogenous 17beta-estrogen and estrogen receptor antagonism did not indicate a significant role on TLR7-induced IFN-alpha production. Our data reveal for the first time a profound sex-dependent pathway of TLR7-induced IFN-alpha with higher production in females. These findings may explain the higher prevalence of SLE in females and the reported decreased therapeutic efficacy of synthetic TLR7 ligands in male individuals.

Adolescent↗