Mechanisms for induction of acquired host immunity by neutrophil peptide defensins

Lillard, James W.; Boyaka, Prosper N.; Chertov, Oleg; Oppenheim, Joost J.; McGhee, Jerry R.

doi:10.1073/pnas.96.2.651

Cited by 279 publications

(220 citation statements)

References 46 publications

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“…uptake and activate human macrophages to kill Trypanosoma cruzi (44). Although these innate and chemotactic molecules directly aid in the accumulation of lymphocytes at infection or immunization sites; lymphocyte recruitment alone does not insure the initiation of an adaptive immune response, particularly not a mucosal immune response (45). Our results and those of others have shown that RANTES incubated with Ag-stimulated lymphocytes significantly enhances Th1-and modestly increases Th2-type cytokine secretion (20).…”

Section: Discussionsupporting

confidence: 67%

RANTES Potentiates Antigen-Specific Mucosal Immune Responses

Lillard

Boyaka

Taub

et al. 2001

The Journal of Immunology

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106

105

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RANTES is produced by lymphoid and epithelial cells of the mucosa in response to various external stimuli and is chemotactic for lymphocytes. The role of RANTES in adaptive mucosal immunity has not been studied. To better elucidate the role of this chemokine, we have characterized the effects of RANTES on mucosal and systemic immune responses to nasally coadministered OVA. RANTES enhanced Ag-specific serum Ab responses, inducing predominately anti-OVA IgG2a and IgG3 followed by IgG1 and IgG2b subclass Ab responses. RANTES also increased Ag-specific Ab titers in mucosal secretions and these Ab responses were associated with increased numbers of Ab-forming cells, derived from mucosal and systemic compartments. Splenic and mucosally derived CD4+ T cells of RANTES-treated mice displayed higher Ag-specific proliferative responses and IFN-γ, IL-2, IL-5, and IL-6 production than control groups receiving OVA alone. In vitro, RANTES up-regulated the expression of CD28, CD40 ligand, and IL-12R by Ag-activated primary T cells from DO11.10 (OVA-specific TCR-transgenic) mice and by resting T cells in a dose-dependent fashion. These studies suggest that RANTES can enhance mucosal and systemic humoral Ab responses through help provided by Th1- and select Th2-type cytokines as well as through the induction of costimulatory molecule and cytokine receptor expression on T lymphocytes. These effects could serve as a link between the initial innate signals of the host and the adaptive immune system.

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Section: Discussionsupporting

confidence: 67%

RANTES Potentiates Antigen-Specific Mucosal Immune Responses

Lillard

Boyaka

Taub

et al. 2001

The Journal of Immunology

Self Cite

106

105

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“…Besides their well established capacity to kill a variety of microbial pathogens, immunomodulating activities have also been described for HNP-1-3. Human neutrophil ␣-defensins show chemotactic activities for T cells and dendritic cells (34), and they enhance the production of antigen-specific antibodies and certain cytokines by immune cells facilitating the initiation of adaptive immune responses (35). Hence, LeTx neutralization by HNP-1-3, in combination with antibiotic eradication of B. anthracis, should be exploited for efficient prevention of fatal anthrax incidences.…”

Section: Discussionmentioning

confidence: 99%

“…35 S-labeled MKK3b was in vitro translated from pcDNA-MKK3b [with the kind help of Jiahuai Han (The Scripps Research Institute, La Jolla, CA)] by using TNT Quick Coupled Transcription͞Translation Systems (Promega). In vitro translated MKK3b was incubated at 37°C for 1 h in reaction buffer (20 mM Hepes and 1 mM CaCl 2 at pH 7.2) with the indicated amounts (see Fig.…”

Section: Methodsmentioning

confidence: 99%

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Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

Kim

Gajendran

Mittrücker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

142

125

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Anthrax caused by Bacillus anthracis represents a major bioterroristic threat. B. anthracis produces lethal toxin (LeTx), a combination of lethal factor (LF) and protective antigen that plays a major role in anthrax pathogenesis. We demonstrate that human neutrophil ␣-defensins are potent inhibitors of LF. The inhibition of LF by human neutrophil protein (HNP-1) was noncompetitive. HNP-1 inhibited cleavage of a mitogen-activated protein kinase kinase and restored impaired mitogen-activated protein kinase signaling in LeTx-treated macrophages. HNP-1 rescued murine macrophages from B. anthracis-induced cytotoxicity, and in vivo treatment with HNP-1-3 protected mice against the fatal consequences of LeTx.defensin ͉ innate immunity ͉ Bacillus anthracis

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“…The role of cationic peptides has been considered of primary significance to the innate immune response. However, it is becoming increasingly apparent that they provide a key link between the innate and adaptive responses (8,9).…”

mentioning

confidence: 99%

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

Bowdish

Davidson

Speert

et al. 2004

The Journal of Immunology

221

229

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LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.

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Mechanisms for induction of acquired host immunity by neutrophil peptide defensins

Abstract: ABSTRACT

Cited by 279 publications

References 46 publications

RANTES Potentiates Antigen-Specific Mucosal Immune Responses

RANTES Potentiates Antigen-Specific Mucosal Immune Responses

Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

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