Mechanisms of Monophosphoryl Lipid A Augmentation of Host Responses to Recombinant HagB from<i>Porphyromonas gingivalis</i>

Yang, Qiu-Bo; Martin, Michael; Michalek, Suzanne M.; Katz, Jannet

doi:10.1128/iai.70.7.3557-3565.2002

Cited by 30 publications

(30 citation statements)

References 61 publications

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“…rHagB was purified as previously described (38,40). Briefly, rHagB was purified from the soluble fraction of lysates of Escherichia coli JM 109 expressing the hagB gene by using a His-bind resin column, according to the manufacturer's instruction (Novagen, Madison, Wis.).…”

Section: Methodsmentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinases and NF-κB in the Regulation of Proinflammatory and Anti-Inflammatory Cytokines byPorphyromonas gingivalisHemagglutinin B

Zhang¹,

Martin²,

Michalek

et al. 2005

Infect Immun

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Hemagglutinin B (HagB) is a nonfimbrial adhesin expressed on the surface of Porphyromonas gingivalis and has been implicated as a potential virulence factor involved in mediating the attachment of the bacteria to host cells. However, the molecular mechanisms underlying host responses to HagB and their roles in pathogenesis have yet to be elucidated. Mitogen-activated protein kinases (MAPKs) are activated following engagement of a variety of cell surface receptors via dual tyrosine and threonine phosphorylation and are thought to be involved in various cellular responses. The purpose of this study was to determine the role of intracellular signaling pathways including the MAPKs and NF-B in regulating the production of proinflammatory and anti-inflammatory cytokines following stimulation of murine macrophages with recombinant HagB (rHagB). Stimulation of peritoneal macrophages with rHagB resulted in the production of the proinflammatory cytokines interleukin-12p40 (IL-12p40), gamma interferon (IFN-␥), and tumor necrosis factor alpha, as well as the anti-inflammatory cytokine IL-10. We also demonstrated the activation of extracellular signal-related kinase (ERK), c-Jun NH 2 -terminal protein kinase (JNK), and p38 MAPKs by rHagB-stimulated macrophages. Furthermore, blocking of the ERK and p38 signaling pathways by using specific inhibitors revealed differential regulatory roles in the rHagB-mediated production of proinflammatory and anti-inflammatory cytokines. ERK and p38 were important in down-regulation of IL-12p40 and IFN-␥ production and up-regulation of IL-10 production. The enhanced levels of IL-12p40 in rHagB-stimulated macrophages by inhibition of ERK or p38 activity were partially attributable to the inhibition of IL-10 production. Moreover, NF-B was found to be critical for up-regulation of IL-12p40 and down-regulation of IL-10 production in rHagB-stimulated macrophages. Taken together, our results demonstrate a role for the p38 and ERK pathways and the transcription factor NF-B in modulating key immunoregulatory cytokines involved in the development of immune responses to P. gingivalis HagB.

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Section: Methodsmentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinases and NF-κB in the Regulation of Proinflammatory and Anti-Inflammatory Cytokines byPorphyromonas gingivalisHemagglutinin B

Zhang¹,

Martin²,

Michalek

et al. 2005

Infect Immun

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“…The adjuvant activities of TLR agonists are usually a manifestation of multiple effects on the antigen presentation-effector apparatus. 55 For instance, monophosphoryl lipid A induces dendritic cell maturation, [56][57][58][59][60] upregulates MHC Class II molecules and CD80 and CD86, [61][62][63] and also indirectly reduces the threshold for activation of T H 1 cells. [64][65][66][67][68][69] …”

Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

“…99 In addition, PAM 2 CSK 4 and MALP-2 induce isotypic switching and differentiation of naïve human B lymphocytes to IgG-secreting plasma cells, 100 indicating a functional association between BCR stimulation and TLR activation. 100 Triacyl PAM 3 CSK 4 has been shown to dramatically enhance MHC Class I-restricted CTL proliferation to an immunodominant influenza peptide Mx [58][59][60][61][62][63][64][65][66] in a human autologous DC/CD8 + T cell co-culture model. 101 The peptide-specific CTLs (assessed by tetramer staining) were also found to be strong producers of IFNγ.…”

Section: Tlr1/tlr2/tlr6 Agonistic Bacterial Lipoteichoic Acid and Lipmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…A lack of participation of these molecules in cell signaling can result in clonal T-cell anergy, antigen-specific hyporesponsiveness or apoptosis [16][17][18][19]. Both CD80 and CD86 costimulatory molecules can be up-regulated upon cell activation; however, their receptor binding properties, kinetics and responsiveness to various stimuli may differ [20,21], and their presence on the various APC may respond differently to the same antigen [22]. It has been shown that CD80 and CD86 can influence the immune response to immunogens by stimulating differentiation of CD4 + T cells into Th1 and Th2 lineages [23,24].…”

Section: Introductionmentioning

confidence: 99%

Role of CD80 and CD86 in host immune responses to the recombinant hemagglutinin domain of Porphyromonas gingivalis gingipain and in the adjuvanticity of cholera toxin B and monophosphoryl lipid A

Zhang

Lewis

Michalek

et al. 2007

Vaccine

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The gingipains of Porphyromonas gingivalis have been implicated in the virulence of this bacterium, and antibodies to the hemagglutinin/adhesin domain (HArep) of the gingipains have been shown to protect against P. gingivalis colonization. However, the cellular mechanisms involved in host responses to HArep have not been elucidated. The purpose of the present study was to determine the functional role of CD80 and CD86 in mediating systemic and mucosal immune responses to the recombinant HArep derived from the gingipain Kgp (Kgp-HArep) after intranasal (i.n.) immunization. We also investigated the effect of the mucosal adjuvants the B subunit of cholera toxin (CTB) and monophosphoryl lipid A (MPL) on the functional role of the costimulatory molecules for the induction of systemic and mucosal responses to Kgp-HArep Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Mechanisms of Monophosphoryl Lipid A Augmentation of Host Responses to Recombinant HagB fromPorphyromonas gingivalis

Cited by 30 publications

References 61 publications

Role of Mitogen-Activated Protein Kinases and NF-κB in the Regulation of Proinflammatory and Anti-Inflammatory Cytokines byPorphyromonas gingivalisHemagglutinin B

Role of Mitogen-Activated Protein Kinases and NF-κB in the Regulation of Proinflammatory and Anti-Inflammatory Cytokines byPorphyromonas gingivalisHemagglutinin B

Potential adjuvantic properties of innate immune stimuli

Role of CD80 and CD86 in host immune responses to the recombinant hemagglutinin domain of Porphyromonas gingivalis gingipain and in the adjuvanticity of cholera toxin B and monophosphoryl lipid A

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