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Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

Bottom Line: In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways.Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway.Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

ABSTRACT
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

No MeSH data available.


Related in: MedlinePlus

Membrane permeabilization of Cl-CATH2 on E. coli (a), S. aureus (b) and C. albicans (c). The left and middle columns represent the microorganisms in absence (−) of Cl-CATH2, under visible light and fluorescence, respectively; the right column is the microorganisms in presence (+) of Cl-CATH2 under fluorescence.
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f4: Membrane permeabilization of Cl-CATH2 on E. coli (a), S. aureus (b) and C. albicans (c). The left and middle columns represent the microorganisms in absence (−) of Cl-CATH2, under visible light and fluorescence, respectively; the right column is the microorganisms in presence (+) of Cl-CATH2 under fluorescence.

Mentions: Cl-CATH2 exerted broad-spectrum but moderate antimicrobial abilities with most MICs ranging from 9.375 to 37.5 μg/ml (Table 1). Although both clinically isolated drug-resistant and standard strains are susceptible to Cl-CATH2, MIC values appear much higher compared to Cc-CATH316, fowlicidin-130 and Pc-CATH124. To determine the possible mechanism underlying Cl-CATH2′s antimicrobial action, its membrane permeabilization effect on E. coli, S. aureus and C. albicans were tested using the classical DNA-binding dye PI. As shown in Fig. 4, the red dye that stains only dead cells with broken membranes was significantly increased, suggesting that the membranes of microorganisms have been disrupted by Cl-CATH2 in a mode similar to that of other amphipathic alpha-helix AMPs.


Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

Membrane permeabilization of Cl-CATH2 on E. coli (a), S. aureus (b) and C. albicans (c). The left and middle columns represent the microorganisms in absence (−) of Cl-CATH2, under visible light and fluorescence, respectively; the right column is the microorganisms in presence (+) of Cl-CATH2 under fluorescence.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508531&req=5

f4: Membrane permeabilization of Cl-CATH2 on E. coli (a), S. aureus (b) and C. albicans (c). The left and middle columns represent the microorganisms in absence (−) of Cl-CATH2, under visible light and fluorescence, respectively; the right column is the microorganisms in presence (+) of Cl-CATH2 under fluorescence.
Mentions: Cl-CATH2 exerted broad-spectrum but moderate antimicrobial abilities with most MICs ranging from 9.375 to 37.5 μg/ml (Table 1). Although both clinically isolated drug-resistant and standard strains are susceptible to Cl-CATH2, MIC values appear much higher compared to Cc-CATH316, fowlicidin-130 and Pc-CATH124. To determine the possible mechanism underlying Cl-CATH2′s antimicrobial action, its membrane permeabilization effect on E. coli, S. aureus and C. albicans were tested using the classical DNA-binding dye PI. As shown in Fig. 4, the red dye that stains only dead cells with broken membranes was significantly increased, suggesting that the membranes of microorganisms have been disrupted by Cl-CATH2 in a mode similar to that of other amphipathic alpha-helix AMPs.

Bottom Line: In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways.Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway.Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

ABSTRACT
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

No MeSH data available.


Related in: MedlinePlus