| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Ebensen, Thomas Guzman, Carlos A. Jha, Mukesh Kumar Srivastava, Sunit Chandel, Himanshu Singh Saha, Bhaskar Pandey, Surya Prakash Shukla, Divanshu Selvaraj, Sathishkumar |
| Description |
Author Affiliation: Pandey SP ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Chandel HS ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Srivastava S ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Selvaraj S ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Jha MK ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Shukla D ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India); Ebensen T ( Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, 38124 Braunschweig, Germany.); Guzman CA ( Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, 38124 Braunschweig, Germany.); Saha B ( National Centre for Cell Science, Ganeshkhind, Pune 411007, India) |
| Abstract |
TLRs recognize pathogen-expressed Ags and elicit host-protective immune response. Although TLR2 forms heterodimers with TLR1 or TLR6, recognizing different ligands, differences in the functions of these heterodimers remain unknown. In this study, we report that in Leishmania major-infected macrophages, the expression of TLR1 and TLR2, but not TLR6, increased; TLR2-TLR2 association increased, but TLR2-TLR6 association diminished. Lentivirus-expressed TLR1-short hairpin RNA (shRNA) or TLR2-shRNA administration reduced, but TLR6-shRNA increased L. major infection in BALB/c mice. Corroboratively, Pam3CSK4 (TLR1-TLR2 ligand) and peptidoglycan (TLR2 ligand) increased L. major infection but reduced TLR9 expression, whereas pegylated bisacycloxypropylcysteine (BPPcysMPEG; TLR2-TLR6 ligand) reduced L. major number in L. major-infected macrophages, accompanied by increased TLR9 expression, higher IL-12 production, and inducible NO synthase expression. Whereas MyD88, Toll/IL-1R adaptor protein, and TNFR- -associated factor 6 recruitments to TLR2 were not different in Pam3CSK4-, peptidoglycan-, or BPPcysMPEG-treated macrophages, only BPPcysMPEG enhanced p38MAPK and activating transcription factor 2 activation. BPPcysMPEG conferred antileishmanial functions to L. major-infected BALB/c-derived T cells in a macrophage-T cell coculture and in BALB/c mice; the protection was TLR6 dependent and IL-12 dependent, and it was accompanied by reduced regulatory T cell number. BPPcysMPEG administration during the priming with fixed L. major protected BALB/c mice against challenge L. major infection; the protection was accompanied by low IL-4 and IL-10, but high IFN-γ productions and reduced regulatory T cells. Thus, BPPcysMPEG, a novel diacylated lipopeptide ligand for TLR2-TLR6 heterodimer, induces IL-12-dependent, inducible NO synthase-dependent, T-reg-sensitive antileishmanial protection. The data reveal a novel dimerization partner-dependent duality in TLR2 function. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| Journal |
The Journal of Immunology |
| Issue Number |
7 |
| Volume Number |
193 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2014-10-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Leishmania Major Immunology Leishmaniasis, Cutaneous Lipopeptides Pharmacology Macrophages, Peritoneal Polyethylene Glycols T-lymphocytes, Regulatory Toll-like Receptor 6 Agonists Animals Cytokines Genetics Gene Expression Regulation Drug Effects Hepatocyte Nuclear Factor 1-beta Pathology Ligands Parasitology Mice Mice, Inbred Balb C Mice, Knockout Nitric Oxide Synthase Type Ii Toll-like Receptor 1 Toll-like Receptor 2 Toll-like Receptor 9 P38 Mitogen-activated Protein Kinases Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
