Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toll-like receptors (TLRs) and complement are 2 components of innate immunity that are critical for first-line host defense and elicitation of adaptive immune responses. Many pathogen-associated molecular patterns activate both TLR and complement, but whether and how these 2 systems, when coactivated in vivo, interact with each other has not been well studied. We demonstrate here a widespread regulation of TLR signaling by complement in vivo. The TLR ligands lipopolysacharride (TLR4), zymosan (TLR2/6), and CpG oligonucleotide (TLR9) caused, in a complement-dependent manner, strikingly elevated plasma interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-1beta, and/or decreased plasma IL-12 levels in mice deficient in the membrane complement inhibitor decay-accelerating factor (DAF). A similar outcome was observed in wild-type mice cotreated with the TLR ligands and cobra venom factor, a potent complement activator. The regulatory effect of complement on TLR-induced cytokine production in vivo was mediated by the anaphylatoxin receptors C5aR and C3aR. Additionally, changes in lipopolysaccharide (LPS)-induced cytokine production in DAF-deficient mice correlated with increased mitogen-activated protein kinase and nuclear factor-kappaB activation in the spleen. These results reveal a strong interaction between complement and TLR signaling in vivo and suggest a novel mechanism by which complement promotes inflammation and modulates adaptive immunity.
 ...
PMID:Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. 1736 30

The contribution of bacterial infection to tumorigenesis is usually ascribed to infection-associated inflammation. An alternate view is that direct interaction of bacteria with tumor cells promotes tumor progression. Here, we show that the microenvironment of large tumors favors bacterial survival, which in turn directly accelerates tumor growth by activating tumor cell Toll-like receptors (TLR). Listeria monocytogenes (Lm) survives in the microenvironment of large but not small tumors, resulting in the promotion of tumor growth. Lm did not affect the percentage of regulatory T cells or myeloid suppressor cells in the tumor. Through TLR2 signaling, Lm activated mitogen-activated protein kinases and nuclear factor-kappaB in tumor cells, resulting in the increased production of nitric oxide and interleukin-6 and increased proliferation of tumor cells. All of these effects were abrogated by silencing expression of TLR2, but not TLR4. The interaction of Helicobacter pylori with tumor cells from gastric carcinoma patients resulted in similar effects. These findings provide a new insight into infection-associated tumorigenesis and illustrate the importance of antibiotic therapy to treat tumors with bacterial infiltration.
 ...
PMID:Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. 3141 50

Liver regeneration following partial hepatectomy (PH) requires several steps including innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor-(TNF-)alpha production by Kupffer cells, although the activation processes are still unknown. Toll-like receptors (TLR) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLR. When the receptors are activated, cells bearing TLR produce various pro-nflammatory cytokines in a MyD88-dependent manner. The authors investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88(-/-) mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of signal transducer and activators of transcription 3 (STAT3) in the liver, and production of TNF-alpha/IL-6 by and activation of NF-kappaB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration, while TLR2, 4 and 9, which recognize Gram-negative and -positive bacterial products, are not essential for NF-kappaB activation and IL-6 production after PH. In conclusion, the TLR/MyD88 pathway is essential for liver restoration after PH, particularly its early phase.
 ...
PMID:Role of innate immune response in liver regeneration. 1756 67

The colonic microbiota is a major modulator of the mucosal immune system; therefore, its manipulation through supplementation with probiotics may significantly affect the host's immune responses. Since different probiotics seem to exert various effects in vivo, we tested the relevance of the autoaggregation phenotype on the intestinal persistence of lactobacilli and their ability to modulate the host's innate immune responses. After 14 days of diet supplementation, the aggregating strain Lactobacillus crispatus M247 but not aggregation-deficient isogenic mutant MU5 was recovered from the feces and colonic mucosa of mice. This observation was confirmed by strain-specific PCR amplification and by Lactobacillus-specific denaturing gradient gel electrophoresis analysis. Indeed, L. crispatus M247 increased Toll-like receptor 2 (TLR2) mRNA levels, while it reduced TLR4 mRNA and protein levels in the colonic mucosa, whereas MU5 was ineffective. In colonic epithelial cells (CMT-93 cells) L. crispatus M247 but not MU5 induced time-dependent extracellular signal-regulated kinase-1 (ERK1) tyrosine phosphorylation and TLR modulation, which were abolished in the presence of PD98059 (an ERK1 inhibitor). To assess the functional relevance of probiotic-induced TLR modulation, we determined the consequences of L. crispatus preexposure on TLR4 (lipopolysaccharide [LPS]) and TLR2 [Pam3Cys-Ser-(Lys)4] ligand-mediated effects in intestinal epithelial cells. Preexposure to L. crispatus M247 blunted LPS-induced interleukin-6 (IL-6) release and inhibition of CMT-93 migration over a wound edge, whereas it enhanced TLR2-mediated IL-10 up-regulation. In summary, the aggregation phenotype is required for L. crispatus persistence in the colon and for modulation of TLR2/TLR4 expression through an ERK-dependent pathway. We speculate that the aggregation phenotype in L. crispatus M247 is required to temper epithelial cell responsiveness to bacterial endotoxins, which thus affects the evolution of intestinal inflammatory processes.
 ...
PMID:Aggregating phenotype in Lactobacillus crispatus determines intestinal colonization and TLR2 and TLR4 modulation in murine colonic mucosa. 1763 14

Vibrio vulnificus is a pathogenic bacterium causing primary septicemia, which follows a classical septic shock pathway, including an overwhelming inflammatory cytokine response. In this study, we identified a putative lipoprotein of V. vulnificus, encoded by the ilpA gene, as one of the surface proteins that specifically reacted with the antibodies raised against outer membrane proteins of V. vulnificus. Using a mutant V. vulnificus in which its ilpA gene was knocked out, we found that IlpA is important in the production of interferon-gamma in human peripheral blood mononuclear cells. Production of tumor necrosis factor-alpha and interleukin-6 is also induced by the recombinant IlpA (rIlpA) in human monocytes. Lipidation of the rIlpA was observed by in vivo labeling in Escherichia coli. Experiments using the mutant IlpA, which is unable to be modified by lipidation, indicate that the lipid moiety of this protein has an essential property for cytokine production in human cells. Pretreatment of monocytes with antibodies against Toll-like receptor 2 (TLR2) inhibited production of both tumor necrosis factor-alpha and interleukin-6. The role of TLR2 in IlpA-induced cytokine production was confirmed by an in vitro assay, in which only the TLR2-expressing cells showed a dramatic induction of nuclear factor-kappaB activity by rIlpA. In addition, rIlpA treatment resulted in induction of TLR2 transcription in human cells. In comparison with the wild type V. vulnificus, the ilpA mutant showed a reduced mortality in mice. These results demonstrate that IlpA of V. vulnificus functions as an immunostimulant to human cells via TLR2.
 ...
PMID:Vibrio vulnificus IlpA-induced cytokine production is mediated by Toll-like receptor 2. 1764 Aug 74

Fibrin sealants have been used in hemostasis and tissue sealing for over 25 years and recent studies have shown them to be an ideal delivery vehicle for cells and bioactive substances. We examined the use of fibrin as a delivery vehicle for the macrophage activator lipoprotein peptide (MALP)-2. MALP-2, secreted by mycoplasma, plays an important role in an early influx of leukocytes and infiltration by monocytes and their subsequent activation into macrophages as detected by their secretion of cytokines and chemoattractants. We first showed that MALP-2 activated several monocytic cell lines by increasing the expression of cytokines and chemoattractants in these cells. Furthermore, using a reverse transcription-polymerase chain reaction approach, we found that MALP-2 affected the gene expression of its own receptors: TLR2 and TLR4 in various cell types including fibroblasts, keratinocytes, and endothelial cells. Furthermore, the conditioned medium, containing secreted cytokines and chemoattractants, collected from monocytes treated with MALP-2 enhanced fibroblast migration using a standard wound culture assay. Next, we examined MALP-2's effect on the human monocyte cell line when it is mixed with fibrin. Monocytes seeded on three-dimensional fibrin containing MALP-2 secreted more cytokines such as interleukin-6, tumor necrosis factor-alpha, and chemoattractants such as macrophage inflammatory protein 1 alpha and monocyte chemoattractant protein 1 when compared with monocytes seeded on three-dimensional fibrin in the absence of MALP-2. This study supports the use of fibrin to deliver MALP-2, and possibly other peptides, in an active form that might enhance wound healing.
 ...
PMID:Fibrin as a delivery vehicle for active macrophage activator lipoprotein-2 peptide: in vitro studies. 1765 96

Toll-like receptors (TLRs) are expressed by human microglia and translate environmental cues into distinct activation programs. We addressed the impact of TLR ligation on the capacity of human microglia to activate and polarize CD4 T cell responses. As microglia exist under distinct states of activation, we examined both ramified and ameboid microglia isolated from adult and fetal CNS, respectively. In vitro, ligation of TLR3 significantly increased major histocompatibility complex and costimulatory molecule expression on adult microglia and induced high levels of interferon-alpha, interleukin-12p40, and interleukin-23. TLR4 and, in particular, TLR2 had a more limited capacity to induce such responses. Coculturing allogeneic CD4 T cells with microglia preactivated with TLR3 did not increase T cell proliferation above basal levels but consistently led to elevated levels of interferon-gamma secretion and Th1 polarization. Fetal microglial TLR3 responses were comparable; in contrast, TLR2 and TLR4 decreased major histocompatibility complex class II expression on fetal cells and reduced CD4 T cell proliferation to levels below those found in untreated cocultures. All 3 TLRs induced comparable interleukin-6 secretion by microglia. Our findings illustrate how activation of human microglia via TLRs, particularly TLR3, can change the profile of local CNS immune responses by translating Th1 polarizing signals to CD4 T cells.
 ...
PMID:Th1 polarization of CD4+ T cells by Toll-like receptor 3-activated human microglia. 1780 15

Toll-like receptor (TLR) agonists, ubiquitously present in the environment, are key players in activating synthesis of cytokines and chemokines that control normal and pathophysiological processes, including multiple inflammatory diseases. TLR2 and TLR4 respond to bacterial cell wall products. We examined the impact of TLR activation on human immune capacity using stimuli ranging from the low levels seen in most environments to the high concentrations widely used for in vitro studies. Peripheral blood mononuclear cells from 117 healthy children were activated with lipopolysaccharide (TLR4 ligand) or peptidoglycan (TLR2 ligand) over a million-fold range of concentrations. Resulting interleukin-6, CCL2, and CCL22 production were quantified by ELISA. The intensity of cytokine production elicited was linearly related to the intensity of the stimulus up to maximal responses. In marked contrast, chemokine production was not linearly related to agonist concentration. Responses rose with increasing stimulation, and then were markedly reduced (40%-100%, p < 0.0001) in response to the high levels of TLR stimulation most commonly cited. Thus, the levels of TLR4 and TLR2 agonists typically used for in vitro interrogation of immune capacity yield results clearly distinct from those obtained using commonly occurring environmental levels of TLR ligands. These findings demonstrate the importance of utilizing TLR ligands at concentrations more closely mimicking environmental levels when assessing immune capacity.
 ...
PMID:Level of Toll-like receptor agonist exposure differentially determines chemokine production in humans. 1782 37

The chemical structure and immunobiological activities of Serratia marcescens lipid A, an active centre of LPS, were investigated. LPS preparations of S. marcescens were extracted using a hot phenol/water method, after which purified lipid A specimens were prepared by weak acid hydrolysis, followed by normal phase and gel filtration chromatographic separation. The lipid A structure was determined by MS to be a diglucosamine backbone with diphosphates and five C(14) normal chain acyl groups, including two acyloxyacyl groups at the 2 and 3 positions of the non-reducing side. S. marcescens lipid A and Escherichia coli-type synthetic lipid A (compound 506) exhibited definite reactivity in Limulus amoebocyte lysate assays. The lethal toxicity of S. marcescens lipid A was nearly comparable to that of compound 506, and both induced nuclear factor-kappaB activation in murine cells via Toll-like receptor (TLR)4/MD-2 but not TLR2, as well as various inflammatory cytokines in peritoneal macrophages of C3H/HeN mice but not C3H/HeJ mice. Furthermore, S. marcescens lipid A induced nearly the same amounts of tumour necrosis factor alpha, interleukin-6, and nitric oxide production by the murine alveolar macrophage cell line MH-S as compared with compound 506. These results indicate that S. marcescens possesses a penta-acylated lipid A, which is nearly identical to E. coli lipid A in regard to biological activities, while it also may be a crucial virulence factor of the bacterium.
 ...
PMID:Chemical structure and immunobiological activity of lipid A from Serratia marcescens LPS. 1796 42

The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC-II)-restricted gamma interferon (IFN-gamma)-producing CD4+ T lymphocytes are poorly understood. We report here that infection of THP-1 cells with B. abortus inhibited expression of MHC-II molecules and antigen (Ag) processing. Heat-killed B. abortus (HKBA) also induced both these phenomena, indicating the independence of bacterial viability and involvement of a structural component of the bacterium. Accordingly, outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, inhibited both MHC-II expression and Ag processing to the same extent as HKBA. Moreover, a synthetic lipohexapeptide that mimics the structure of the protein lipid moiety also inhibited MHC-II expression, indicating that any Brucella lipoprotein could down-modulate MHC-II expression and Ag processing. Inhibition of MHC-II expression and Ag processing by either HKBA or lipidated Omp19 (L-Omp19) depended on Toll-like receptor 2 and was mediated by interleukin-6. HKBA or L-Omp19 also inhibited MHC-II expression and Ag processing of human monocytes. In addition, exposure to the synthetic lipohexapeptide inhibited Ag-specific T-cell proliferation and IFN-gamma production of peripheral blood mononuclear cells from Brucella-infected patients. Together, these results indicate that there is a mechanism by which B. abortus may prevent recognition by T cells to evade host immunity and establish a chronic infection.
 ...
PMID:Brucella abortus inhibits major histocompatibility complex class II expression and antigen processing through interleukin-6 secretion via Toll-like receptor 2. 1798 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>