Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism

Lin, Wei; Gao, Jiuxiang; Zhang, Shumin; Wu, Sijin; Xie, Zeping; Ling, Guiying; Kuang, Yi‐Qun; Yang, Yongliang; Yu, Haining; Wang, Yipeng

doi:10.1074/jbc.m115.642645

Cited by 101 publications

(187 citation statements)

References 45 publications

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“…Similar to the extensive research on antimicrobial activity, LPS neutralization has been shown in multiple studies for at least 13 different cathelicidins from 9 different species18434557585960616263646566. Therefore, it is thought to be one of the main cathelicidin functions.…”

Section: Discussionmentioning

confidence: 84%

Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis

Coorens

Scheenstra

Veldhuizen

et al. 2017

Sci Rep

101

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Cathelicidins are short cationic peptides initially described as antimicrobial peptides, which can also modulate the immune system. Because most findings have been described in the context of human LL-37 or murine CRAMP, or have been investigated under varying conditions, it is unclear which functions are cathelicidin specific and which functions are general cathelicidin properties. This study compares 12 cathelicidins from 6 species under standardized conditions to better understand the conservation of cathelicidin functions. Most tested cathelicidins had strong antimicrobial activity against E. coli and/or MRSA. Interestingly, while more physiological culture conditions limit the antimicrobial activity of almost all cathelicidins against E. coli, activity against MRSA is enhanced. Seven out of 12 cathelicidins were able to neutralize LPS and another 7 cathelicidins were able to neutralize LTA; however, there was no correlation found with LPS neutralization. In contrast, only 4 cathelicidins enhanced DNA-induced TLR9 activation. In conclusion, these results provide new insight in the functional differences of cathelicidins both within and between species. In addition, these results underline the importance not to generalize cathelicidin functions and indicates that caution should be taken in extrapolating results from LL-37- or CRAMP-related studies to other animal settings.

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Section: Discussionmentioning

confidence: 84%

Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis

Coorens

Scheenstra

Veldhuizen

et al. 2017

Sci Rep

101

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“…LLKKK18 induces rapid resolution of the inflammatory stage through early M2 macrophage recruitment and stimulates angiogenesis. Yet another HDP that exhibits potent anti-inflammatory activity by inhibiting LPSinduced NO and pro-inflammatory cytokine including TNF-α, IL-6, and IL-1β production is a cathelicidin from the sea snake Hydrophis cyanocinctus [74]. The mode of action is reported to be competitive binding to the Toll-TLR4/MD2 complex, preventing LPS attachment and subsequent activation of LPS-induced inflammatory response pathways.…”

Section: Pro-and Anti-inflammatory Activitiesmentioning

confidence: 99%

Immunomodulatory effects of anti-microbial peptides

Ötvös¹

2016

Acta Microbiologica et Immunologica Hungarica

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Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro-and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

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“…In addition, venom has been shown to have pro- and anti-inflammatory properties and has been shown to regulate the expression of inflammatory mediators such as IL-1β, IL-6, IL-10, IL-22, TNF-α, PGD2, PGE2, and TXA2 [18,19,21,41,42,43,44]. In this study, we constructed and screened an H. cyanocinctus venom gland T7 phage display library and discovered H-TL1, a natural peptide with antagonizing effects against TNF-α.…”

Section: Discussionmentioning

confidence: 99%

“…Venom from sea snakes is more streamlined and stable than that from land snakes [20], and Hydrophis cyanocinctus , a primary sea snake species in China, has been used to treat rheumatism for centuries. Wei et al reported a novel cathelicidin (Hc-CATH) from the H. cyanocinctus sea snake that exhibits potent anti-inflammatory activity by inhibiting pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [21]. Furthermore, hydrostatin-SN1, which was identified by screening a H. cyanocinctus venom gland T7 phage display library, exhibited significant anti-inflammatory activity in a DSS-induced acute colitis mouse model [22].…”

Section: Introductionmentioning

confidence: 99%

Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea

Wang

Huang

Liu

et al. 2016

IJMS

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Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-α and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-α and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-α in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-α/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-α-associated inflammatory diseases.

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Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism

Cited by 101 publications

References 45 publications

Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis

Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis

Immunomodulatory effects of anti-microbial peptides

Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea

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