Human beta-defensin-2 and -3 enhance pro-inflammatory cytokine expression induced by TLR ligands via ATP-release in a P2X7R dependent manner

Wanke, Daniela; Mauch-Mücke, Katrin; Holler, Ernst; Hehlgans, Thomas

doi:10.1016/j.imbio.2016.06.006

Cited by 22 publications

(22 citation statements)

References 24 publications

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“…mBD-2 activates immature dendritic cells, functioning as a TLR4 ligand and upregulating co-stimulatory molecules toward to a TH1 polarized response (130). In addition, hBD-3 activates monocytes in a TLR1/2 dependent fashion (131), whereas hBD-2 and -3 increase pro-inflammatory cytokine release from TLRstimulated macrophages by ATP release and P2X7 activation (132). Interestingly, hBD-1, -2, and -3 all stimulate cytokine release from human peripheral blood mononuclear cells, with each β-defensin stimulating a unique array of cytokines (133).…”

Section: β-Defensinsmentioning

confidence: 99%

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

et al. 2020

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Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and-negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.

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Section: β-Defensinsmentioning

confidence: 99%

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

et al. 2020

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“…The hBD3 possess a broad spectrum of antimicrobial activity against many pathogenic microbes, including Grampositive and Gram-negative bacteria, fungi (Batoni et al, 2006), and different viruses such as HIV, IAV, VSV, HBV, HPV, HSV, CVB3 and vaccinia virus (Ding et al, 2009;Hazrati et al, 2006;Jiang et al, 2015;Wilson et al, 2013). It is involved in different infectious diseases progress and immune regulations (Bian et al, 2016;Li et al, 2016;Szekeres et al, 2016;Wanke et al, 2016;Xu et al, 2016). It has been reported that hBD3 can block IAV, HSV, and HIV entry into cells by cross linking and immobilizing viral surface proteins (Hazrati et al, 2006;Leikina et al, 2005;Quinones-Mateu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Induction and antiviral activity of human β-defensin 3 in intestinal cells with picornavirus infection

W¹,

Z²,

Zhang³

et al. 2018

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Antimicrobial peptides produced by epithelial and immune cells protect tissues from various infections. Whether enterovirus infection leads to stimulation of antimicrobial peptide expression is unknown. We examined antimicrobial peptide mRNA and protein production in HT-29 colon adenocarcinoma cells infected with picornaviruses. The antiviral activity of increased antimicrobial peptide production was evaluated by using a recombinant peptide and corresponding gene overexpression. Enterovirus infection enhanced both the mRNA expression and secretion of human β-defensin (hBD) 3 in intestinal epithelial cells but did not increase expression of human neutrophil peptide 1-3 (HNP 1-3), HNP4, human defensin 5 (HD5), HD6, hBD1, hBD2, and hBD5. The recombinant but not the intracellularly overexpressed hBD3 inhibited enterovirus (EV) 71, coxsackievirus A16 (CVA16), CVB5 and poliovirus 1 (PV1) infecting HT-29 cells. Our results suggest that enterovirus infection induces hBD3 production in human intestinal epithelial cells and that hBD3 can exert extracellular anti-enterovirus activity.

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“…LPS, on the other hand, acts primarily via TLR‐4 which further transduces through MyD88 or TRIF (which does not require PI(4,5)P 2 ) to activate NF‐κB, implying that the role of PI(4,5)P 2 does not appear critical and, hence, are not affected by wortmannin, neomycin or staurosporine. PI(4,5)P 2 binding of HBD‐3 might also explain IL‐1β induction and co‐stimulatory marker expression via ATP‐gated channel P2X 7 which is directly regulated by PI(4,5)P 2 …”

Section: Discussionmentioning

confidence: 99%

“…In addition, HBD‐3 induces proinflammatory cytokine release in monocytes, macrophages, and keratinocytes as well as promotes iDC and monocyte maturation by activating NF‐κB, possibly through CCR2/6‐PLC‐dependent and/or TLR‐1/2‐dependent pathways . HBD‐3 can also induce co‐stimulatory marker expression via activation of ATP‐gated P2X 7 channel . In contrast, it was later demonstrated that the HBD‐3‐induced NF‐κB activation was not inhibited by a G‐protein inhibitor pertussis toxin, a MyD88 inhibitor or TLR‐1 or TRIF inhibitor, suggesting a G‐coupled protein‐ and TLR‐independent mechanism .…”

Section: Introductionmentioning

confidence: 99%

“…6,23,26,27 HBD-3 can also induce co-stimulatory marker expression via activation of ATP-gated P2X 7 channel. 28,29 In contrast, it was later demonstrated that the HBD-3-induced NF-jB activation was not inhibited by a G-protein inhibitor pertussis toxin, a MyD88 inhibitor or TLR-1 or TRIF inhibitor, suggesting a G-coupled protein-and TLR-independent mechanism. 30 Alternatively, the authors suggested NF-jB was noncanonically activated through PI3K-Akt signaling, 30 although the detailed mechanism of PI3K-Akt stimulation by HBD-3 remained unclear.…”

Section: Introductionmentioning

confidence: 99%

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Importance of phosphoinositide binding by human β‐defensin 3 for Akt‐dependent cytokine induction

2017

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Host defense peptides (HDPs) are well-characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β-defensin 3 (HBD-3) belongs to a well-known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co-stimulatory marker expression. HBD-3-stimulated cytokine induction is NF-κB-dependent and was initially suggested to act via G protein-coupled C-C chemokine receptor phospholipase C (PLC) and/or Toll-like receptor signaling. Subsequent pharmacological inhibition, however, revealed that NF-κB activation by HBD-3 is receptor-independent and instead involves the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway, the mechanism of which remains undetermined. Recently, we have shown that HBD-3 can enter mammalian cells and bind to inner membrane phosphoinositide 4,5-bisphosphate [PI(4,5)P], an important second lipid messenger of PLC and PI3K-Akt pathways. In this study, we report that the interaction of HBD-3 with PI(4,5)P is important for PI3K-Akt-NF-κΒ-mediated induction of tumor necrosis factor and interleukin-6. These data provide insights into the mechanism of immunomodulation by HBD-3, and more generally, highlight the complex multifaceted signaling roles of HDPs in innate defense. Furthermore, it is suggested that the proposed mode of action may be conserved in other HDPs.

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Human beta-defensin-2 and -3 enhance pro-inflammatory cytokine expression induced by TLR ligands via ATP-release in a P2X7R dependent manner

Cited by 22 publications

References 24 publications

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

Induction and antiviral activity of human β-defensin 3 in intestinal cells with picornavirus infection

Importance of phosphoinositide binding by human β‐defensin 3 for Akt‐dependent cytokine induction

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