Pub Date : 2006-10-01DOI: 10.1177/09680519060120050601
S. Santos-Sierra, D. Golenbock, P. Henneke
Streptococcus pneumoniae and Streptococcus agalactiae cause distinct infectious diseases in small children. Similarly, these bacteria elicit very different host-cell responses in vitro. Inactivated S. agalactiae by far exceeds S. pneumoniae in the activation of inflammatory cytokines and upstream signaling intermediates such as the MAP kinase JNK. The inflammatory response to both Streptococcus spp. is mediated by MyD88, an essential adapter protein of Toll-like receptors (TLRs), although the specific TLRs that are involved have not been fully resolved. Furthermore, during logarithmic growth, S. pneumoniae releases pneumolysin that interacts with TLR4 whereas S. agalactiae releases diacylated molecules that interact with TLR2/6. Interaction of these soluble bacterial products with their cognate TLRs is critical for limiting bacterial dissemination and and systemic inflammation in mice. This might be due, in part, to TLR-mediated apoptosis induced by these factors. In conclusion related streptococcal species induce specific events in TLR-mediated signal transduction. Comparative analysis of the host-cell response to these bacteria reveals molecules such as JNK as valuable targets for adjunctive sepsis therapy.
{"title":"Toll-like receptor-dependent discrimination of streptococci","authors":"S. Santos-Sierra, D. Golenbock, P. Henneke","doi":"10.1177/09680519060120050601","DOIUrl":"https://doi.org/10.1177/09680519060120050601","url":null,"abstract":"Streptococcus pneumoniae and Streptococcus agalactiae cause distinct infectious diseases in small children. Similarly, these bacteria elicit very different host-cell responses in vitro. Inactivated S. agalactiae by far exceeds S. pneumoniae in the activation of inflammatory cytokines and upstream signaling intermediates such as the MAP kinase JNK. The inflammatory response to both Streptococcus spp. is mediated by MyD88, an essential adapter protein of Toll-like receptors (TLRs), although the specific TLRs that are involved have not been fully resolved. Furthermore, during logarithmic growth, S. pneumoniae releases pneumolysin that interacts with TLR4 whereas S. agalactiae releases diacylated molecules that interact with TLR2/6. Interaction of these soluble bacterial products with their cognate TLRs is critical for limiting bacterial dissemination and and systemic inflammation in mice. This might be due, in part, to TLR-mediated apoptosis induced by these factors. In conclusion related streptococcal species induce specific events in TLR-mediated signal transduction. Comparative analysis of the host-cell response to these bacteria reveals molecules such as JNK as valuable targets for adjunctive sepsis therapy.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"307 - 312"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-10-01DOI: 10.1177/09680519060120050301
Suresh Kumar, R. Jack
Activation of the immune system requires that the presence of an incipient infection first be detected. This essential step is carried out by tissue macrophages, which alert innate immunity, and by dendritic cells whih alert the adaptive immune system. Both of these sentinel cell types are derived from circulating precursors known as blood monocytes. Here we briefly review current work which has recently expanded our understanding of the origin of blood monocytes and of the factors governing their further differentiation into tissue sentinels.
{"title":"Invited review: Origin of monocytes and their differentiation to macrophages and dendritic cells","authors":"Suresh Kumar, R. Jack","doi":"10.1177/09680519060120050301","DOIUrl":"https://doi.org/10.1177/09680519060120050301","url":null,"abstract":"Activation of the immune system requires that the presence of an incipient infection first be detected. This essential step is carried out by tissue macrophages, which alert innate immunity, and by dendritic cells whih alert the adaptive immune system. Both of these sentinel cell types are derived from circulating precursors known as blood monocytes. Here we briefly review current work which has recently expanded our understanding of the origin of blood monocytes and of the factors governing their further differentiation into tissue sentinels.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"31 1","pages":"278 - 284"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-10-01DOI: 10.1177/09680519060120050701
M. Alderson, P. Mcgowan, J. Baldridge, P. Probst
Monophosphoryl lipid A (MPL®) is a potent vaccine adjuvant derived from Salmonella minnesota that was recently licensed in Europe as a component of an improved vaccine for hepatitis B (Fendrix®). MPL, like lipopolysaccharide from which it is derived, signals via the TLR4/MD-2 complex. We have produced a series of synthetic Toll-like receptor 4 (TLR4) agonists that are based upon the structure of the major hexa-acylated congener contained within MPL. These TLR4 agonists, termed the aminoalkyl glucosaminide phosphates (AGPs), stimulate the production of various cytokines by human peripheral blood mononuclear cells in vitro and up-regulate cell surface markers on monocytes, NK cells and B cells. In addition, AGPs provide non-specific resistance to challenge with viral and bacterial pathogens when administered to the upper airways of mice. Structure—activity relationship studies have shown that the activation of innate immune effectors by AGPs depends primarily on the length of the secondary acyl chains and the nature of the functional group attached to the aglycon component. Moreover, AGPs can act as potent adjuvants for mucosal administration of vaccine antigens, enhancing both antigen-specific antibody and cell-mediated immune responses. Thus, by combining the adjuvant and non-specific resistance induction properties of AGPs it may be possible to generate mucosal vaccines that provide innate protection immediately following administration together with long-term acquired immunity.
{"title":"TLR4 agonists as immunomodulatory agents","authors":"M. Alderson, P. Mcgowan, J. Baldridge, P. Probst","doi":"10.1177/09680519060120050701","DOIUrl":"https://doi.org/10.1177/09680519060120050701","url":null,"abstract":"Monophosphoryl lipid A (MPL®) is a potent vaccine adjuvant derived from Salmonella minnesota that was recently licensed in Europe as a component of an improved vaccine for hepatitis B (Fendrix®). MPL, like lipopolysaccharide from which it is derived, signals via the TLR4/MD-2 complex. We have produced a series of synthetic Toll-like receptor 4 (TLR4) agonists that are based upon the structure of the major hexa-acylated congener contained within MPL. These TLR4 agonists, termed the aminoalkyl glucosaminide phosphates (AGPs), stimulate the production of various cytokines by human peripheral blood mononuclear cells in vitro and up-regulate cell surface markers on monocytes, NK cells and B cells. In addition, AGPs provide non-specific resistance to challenge with viral and bacterial pathogens when administered to the upper airways of mice. Structure—activity relationship studies have shown that the activation of innate immune effectors by AGPs depends primarily on the length of the secondary acyl chains and the nature of the functional group attached to the aglycon component. Moreover, AGPs can act as potent adjuvants for mucosal administration of vaccine antigens, enhancing both antigen-specific antibody and cell-mediated immune responses. Thus, by combining the adjuvant and non-specific resistance induction properties of AGPs it may be possible to generate mucosal vaccines that provide innate protection immediately following administration together with long-term acquired immunity.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"313 - 319"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050701","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-10-01DOI: 10.1177/09680519060120050401
Q. Nhu, N. Cuesta, S. Vogel
Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription factors, the interferon regulatory factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2—/ — macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2—/ — macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.
{"title":"Transcriptional regulation of lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) expression in murine macrophages: role of interferon regulatory factors 1 (IRF-1) and 2 (IRF-2)","authors":"Q. Nhu, N. Cuesta, S. Vogel","doi":"10.1177/09680519060120050401","DOIUrl":"https://doi.org/10.1177/09680519060120050401","url":null,"abstract":"Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription factors, the interferon regulatory factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2—/ — macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2—/ — macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"285 - 295"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040301
A. Erdoğan, C. Schaefer, A. Most, M. Schaefer, K. Mayer, H. Tillmanns, C. Kuhlmann
The adhesion of monocytes to the endothelium and their proliferation in the subendothelial space play an important role in atherosclerosis. Since the proliferation and migration of cells are influenced by the activity of ion channels, the aim of this study was to examine whether barium chloride (Ba2+)-sensitive potassium channels (KiCa) are involved in lipopolysaccharide (LPS)-induced proliferation of monocytic U937 cells, and in the adhesion of these cells to endothelial cells. The adhesion of LPS-stimulated U937 cells to endothelial cells reached a maximum at a concentration of 5 µg/ml. This effect of LPS was completely abolished in the presence of Ba2+ (100 µmol/l). In addition, LPS-induced proliferation was significantly reduced by Ba 2+ (control, 100%; LPS 5 µg/ml, 175%; LPS + Ba2+ 100 µmol/l, 136%; n = 12, P < 0.05). To examine whether KiCa are activated by LPS, changes of U937 membrane potential were determined. LPS (5 µg/ml) caused a hyperpolarization of U937 cells indicating a flux of K+ ions out of the cells. This effect was completely blocked by Ba2+ (100 µmol/l). In conclusion, we demonstrate that LPS activates KiCa in U937 cells, which is responsible for LPS-induced adhesion of these cells to endothelial cells, and to the proliferation of U937 cells.
{"title":"Lipopolysaccharide-induced proliferation and adhesion of U937 cells to endothelial cells involves barium chloride sensitive hyperpolarization","authors":"A. Erdoğan, C. Schaefer, A. Most, M. Schaefer, K. Mayer, H. Tillmanns, C. Kuhlmann","doi":"10.1177/09680519060120040301","DOIUrl":"https://doi.org/10.1177/09680519060120040301","url":null,"abstract":"The adhesion of monocytes to the endothelium and their proliferation in the subendothelial space play an important role in atherosclerosis. Since the proliferation and migration of cells are influenced by the activity of ion channels, the aim of this study was to examine whether barium chloride (Ba2+)-sensitive potassium channels (KiCa) are involved in lipopolysaccharide (LPS)-induced proliferation of monocytic U937 cells, and in the adhesion of these cells to endothelial cells. The adhesion of LPS-stimulated U937 cells to endothelial cells reached a maximum at a concentration of 5 µg/ml. This effect of LPS was completely abolished in the presence of Ba2+ (100 µmol/l). In addition, LPS-induced proliferation was significantly reduced by Ba 2+ (control, 100%; LPS 5 µg/ml, 175%; LPS + Ba2+ 100 µmol/l, 136%; n = 12, P < 0.05). To examine whether KiCa are activated by LPS, changes of U937 membrane potential were determined. LPS (5 µg/ml) caused a hyperpolarization of U937 cells indicating a flux of K+ ions out of the cells. This effect was completely blocked by Ba2+ (100 µmol/l). In conclusion, we demonstrate that LPS activates KiCa in U937 cells, which is responsible for LPS-induced adhesion of these cells to endothelial cells, and to the proliferation of U937 cells.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"224 - 230"},"PeriodicalIF":0.0,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120040301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040201
M. Trent, Christopher M. Stead, A. Tran, Jessica V. Hankins
Lipopolysaccharide or LPS is localized to the outer leaflet of the outer membrane and serves as the major surface component of the bacterial cell envelope. This remarkable glycolipid is essential for virtually all Gram-negative organisms and represents one of the conserved microbial structures responsible for activation of the innate immune system. For these reasons, the structure, function, and biosynthesis of LPS has been an area of intense research. The LPS of a number of bacteria is composed of three distinct regions — lipid A, a short core oligosaccharide, and the O-antigen polysaccharide. The lipid A domain, also known as endotoxin, anchors the molecule in the outer membrane and is the bioactive component recognized by TLR4 during human infection. Overall, the biochemical synthesis of lipid A is a highly conserved process; however, investigation of the lipid A structures of various organisms shows an impressive amount of diversity. These differences can be attributed to the action of latent enzymes that modify the canonical lipid A molecule. Variation of the lipid A domain of LPS serves as one strategy utilized by Gram-negative bacteria to promote survival by providing resistance to components of the innate immune system and helping to evade recognition by TLR4. This review summarizes the biochemical machinery required for the production of diverse lipid A structures of human pathogens and how structural modification of endotoxin impacts pathogenesis.
{"title":"Invited review: Diversity of endotoxin and its impact on pathogenesis","authors":"M. Trent, Christopher M. Stead, A. Tran, Jessica V. Hankins","doi":"10.1177/09680519060120040201","DOIUrl":"https://doi.org/10.1177/09680519060120040201","url":null,"abstract":"Lipopolysaccharide or LPS is localized to the outer leaflet of the outer membrane and serves as the major surface component of the bacterial cell envelope. This remarkable glycolipid is essential for virtually all Gram-negative organisms and represents one of the conserved microbial structures responsible for activation of the innate immune system. For these reasons, the structure, function, and biosynthesis of LPS has been an area of intense research. The LPS of a number of bacteria is composed of three distinct regions — lipid A, a short core oligosaccharide, and the O-antigen polysaccharide. The lipid A domain, also known as endotoxin, anchors the molecule in the outer membrane and is the bioactive component recognized by TLR4 during human infection. Overall, the biochemical synthesis of lipid A is a highly conserved process; however, investigation of the lipid A structures of various organisms shows an impressive amount of diversity. These differences can be attributed to the action of latent enzymes that modify the canonical lipid A molecule. Variation of the lipid A domain of LPS serves as one strategy utilized by Gram-negative bacteria to promote survival by providing resistance to components of the innate immune system and helping to evade recognition by TLR4. This review summarizes the biochemical machinery required for the production of diverse lipid A structures of human pathogens and how structural modification of endotoxin impacts pathogenesis.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"205 - 223"},"PeriodicalIF":0.0,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120040201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040501
M. Finkelman, Steven J. Lempitski, J. Slater
Background: Allergen extracts contain variable quantities of bacterial endotoxin. Recent studies have suggested that (1→3)-β-D-glucans (β-glucans), also microbial cell wall components, may have adjuvant properties that could affect allergen immunotherapy. Objective: To determine the quantities of β-glucans in standardized allergen extracts. Materials and Methods : Ninety-four lots of 13 standardized allergen extracts were tested for β-glucan content by Glucatell assay, and for endotoxin content by a specific, chromogenic formulation of the Limulus amebocyte lysate test. Results: Standardized allergen extracts contain variable quantities of endotoxins and β-glucans. As in our previous work, endotoxin activity was greatest in cat pelt and Dermatophagoides farinae, and least in the pollens. There was no correlation between endotoxin and β-glucan levels (r = 0.1887; P = 0.07). β-Glucan content was highest for grass pollen (median content, 10.6 ng/ml; range, 0.4—41.8 ng/ml), ragweed pollen (32.9 ng/ml; range, 6.5—41.2 ng/ml), and cat pelt (25.5 ng/ml; range, 16.7—41.1 ng/ml), and lowest for cat hair (4.9 ng/ml; range, 1.2—10.3 ng/ml), D. farinae (1.2 ng/ml; range, 0.4—5.2 ng/ml) and Dermatophagoides pteronyssinus (1.8 ng/ml; range, 0.4—6.7 ng/ml). Conclusions: β-Glucans are present in standardized allergen extracts. The effects of these quantities of β-glucans on allergen immunotherapy and allergen skin testing require further study.
{"title":"β-Glucans in standardized allergen extracts","authors":"M. Finkelman, Steven J. Lempitski, J. Slater","doi":"10.1177/09680519060120040501","DOIUrl":"https://doi.org/10.1177/09680519060120040501","url":null,"abstract":"Background: Allergen extracts contain variable quantities of bacterial endotoxin. Recent studies have suggested that (1→3)-β-D-glucans (β-glucans), also microbial cell wall components, may have adjuvant properties that could affect allergen immunotherapy. Objective: To determine the quantities of β-glucans in standardized allergen extracts. Materials and Methods : Ninety-four lots of 13 standardized allergen extracts were tested for β-glucan content by Glucatell assay, and for endotoxin content by a specific, chromogenic formulation of the Limulus amebocyte lysate test. Results: Standardized allergen extracts contain variable quantities of endotoxins and β-glucans. As in our previous work, endotoxin activity was greatest in cat pelt and Dermatophagoides farinae, and least in the pollens. There was no correlation between endotoxin and β-glucan levels (r = 0.1887; P = 0.07). β-Glucan content was highest for grass pollen (median content, 10.6 ng/ml; range, 0.4—41.8 ng/ml), ragweed pollen (32.9 ng/ml; range, 6.5—41.2 ng/ml), and cat pelt (25.5 ng/ml; range, 16.7—41.1 ng/ml), and lowest for cat hair (4.9 ng/ml; range, 1.2—10.3 ng/ml), D. farinae (1.2 ng/ml; range, 0.4—5.2 ng/ml) and Dermatophagoides pteronyssinus (1.8 ng/ml; range, 0.4—6.7 ng/ml). Conclusions: β-Glucans are present in standardized allergen extracts. The effects of these quantities of β-glucans on allergen immunotherapy and allergen skin testing require further study.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"241 - 245"},"PeriodicalIF":0.0,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120040501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040101
K. Miyake
The Toll family of receptors recognizes a variety of microbial products and triggers immune responses. Recent progress has revealed a requirement for accessory molecules in microbial recognition by Toll-like receptors. Lipopolysaccharide (LPS) recognition requires LPS binding protein (LBP), CD14, and MD-2. MD-2 is directly involved in ligand-binding and subsequent receptor activation, whereas LBP and CD14 control ligand presentation to the receptor complex, Toll-like receptor (TLR4)/MD-2. CD14 and LBP influence the amplitude of LPS responses and LPS-induced type I interferon production. TLR2 is also reported to require similar accessory molecules. Innate immune responses to microbial products driven by TLRs are controlled by accessory molecules working upstream of TLRs.
{"title":"Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors","authors":"K. Miyake","doi":"10.1177/09680519060120040101","DOIUrl":"https://doi.org/10.1177/09680519060120040101","url":null,"abstract":"The Toll family of receptors recognizes a variety of microbial products and triggers immune responses. Recent progress has revealed a requirement for accessory molecules in microbial recognition by Toll-like receptors. Lipopolysaccharide (LPS) recognition requires LPS binding protein (LBP), CD14, and MD-2. MD-2 is directly involved in ligand-binding and subsequent receptor activation, whereas LBP and CD14 control ligand presentation to the receptor complex, Toll-like receptor (TLR4)/MD-2. CD14 and LBP influence the amplitude of LPS responses and LPS-induced type I interferon production. TLR2 is also reported to require similar accessory molecules. Innate immune responses to microbial products driven by TLRs are controlled by accessory molecules working upstream of TLRs.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"195 - 204"},"PeriodicalIF":0.0,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120040101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040601
E. Pietras, Supriya K. Saha, Genhong Cheng
Type I interferons (IFNs) were first described several decades ago as soluble factors that were capable of `interfering' with viral replication when added to infected cells. Type I IFNs have been shown to be induced by recognition of viral DNA and RNA via three distinct pathways: (i) a TRIFdependent pathway in macrophages via TLRs 3 and 4; (ii) a MyD88-dependent pathway in plasmacytoid dendritic cells (pDCs) via TLRs 7/8 and 9; and (iii) an intracellular recognition pathway utilizing the cytoplasmic receptors RIG-I/MDA5. Interestingly, these viral recognition pathways converge on TRAF3, which induces interferon through the activation of IRF3 or IRF7 by the TBK-1 and IKKi complexes. While type I IFN has been traditionally associated with antiviral responses, recent studies have demonstrated that many bacteria also induce type I interferon responses. The mechanisms of type I IFN induction and its role in host defense, however, are largely unclear. Studies with the Gram-positive intracellular bacterium Listeria monocytogenes indicated that it may trigger type I IFN induction through novel TLR-independent intracellular receptors and type I IFN may play a detrimental role to host response against listerial infection. In this article, we summarize some of these findings and discuss the functional differences of type I IFNs in bacterial and viral infections.
{"title":"The interferon response to bacterial and viral infections","authors":"E. Pietras, Supriya K. Saha, Genhong Cheng","doi":"10.1177/09680519060120040601","DOIUrl":"https://doi.org/10.1177/09680519060120040601","url":null,"abstract":"Type I interferons (IFNs) were first described several decades ago as soluble factors that were capable of `interfering' with viral replication when added to infected cells. Type I IFNs have been shown to be induced by recognition of viral DNA and RNA via three distinct pathways: (i) a TRIFdependent pathway in macrophages via TLRs 3 and 4; (ii) a MyD88-dependent pathway in plasmacytoid dendritic cells (pDCs) via TLRs 7/8 and 9; and (iii) an intracellular recognition pathway utilizing the cytoplasmic receptors RIG-I/MDA5. Interestingly, these viral recognition pathways converge on TRAF3, which induces interferon through the activation of IRF3 or IRF7 by the TBK-1 and IKKi complexes. While type I IFN has been traditionally associated with antiviral responses, recent studies have demonstrated that many bacteria also induce type I interferon responses. The mechanisms of type I IFN induction and its role in host defense, however, are largely unclear. Studies with the Gram-positive intracellular bacterium Listeria monocytogenes indicated that it may trigger type I IFN induction through novel TLR-independent intracellular receptors and type I IFN may play a detrimental role to host response against listerial infection. In this article, we summarize some of these findings and discuss the functional differences of type I IFNs in bacterial and viral infections.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"246 - 250"},"PeriodicalIF":0.0,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120040601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-08-01DOI: 10.1177/09680519060120040401
Joanna L. Shoenfelt, M. Fenton
Engagement of Toll-like receptor (TLR) proteins activates multiple signal transduction pathways. Previous studies demonstrated that TLR2 and TLR4 engagement leads to rapid phosphorylation of the transcription factor STAT1 at serine 727 (Ser-727 STAT1) in murine macrophages. Only TLR4 engagement induced STAT1 phosphorylation at tyrosine 701, although this response was delayed compared with Ser-727 STAT1 phosphorylation. Unlike other cell types, the p38 mitogen-activated protein kinase was necessary, but not sufficient, for TLR-induced phosphorylation of Ser-727 STAT1 in macrophages. We and others had previously shown that Ser-727 STAT1 phosphorylation could be blocked by rottlerin, an inhibitor of protein kinase C-δ (PKC—δ). Here we report that peritoneal exudate macrophages from PKC-δ-deficient mice can be activated through TLR2 and TLR4 to elicit rapid phosphorylation of Ser-727 STAT1, which was blocked by both rottlerin and the p38 inhibitor SB203580, but not by the pan-PKC inhibitor bisindoylmaleamide. Furthermore, both normal and PKC-δ-deficient macrophages secreted comparable amounts of IL-6, IP-10, and RANTES following TLR engagement. In contrast, IFN-γ-induced STAT1 serine phosphorylation was independent of both PKC-δ and p38. Overall, these studies demonstrate that a PKC-δindependent signaling pathway downstream of both TLR2 and TLR4 is necessary for Ser-727 STAT1 phosphorylation in primary murine macrophages.
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