TLR2 dimer-specific ligands selectively activate protein kinase C isoforms in Leishmania infection
| Autor: | Arkajyoti Mukherjee, Jagneswar Dandapat, Sayoni Roy, Bhaskar Saha, Ashok Patidar, Arup Sarkar, Neelam Bodhale |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Immunology Leishmaniasis Cutaneous Ligands Cell membrane 03 medical and health sciences Mice 0302 clinical medicine medicine Immunology and Allergy Animals Protein Isoforms Phosphorylation Receptor Protein kinase C Protein Kinase C Calcium signaling Toll-like receptor Mice Inbred BALB C Chemistry Macrophages Original Articles Toll-Like Receptor 2 Cell biology TLR2 030104 developmental biology medicine.anatomical_structure Cytokines 030215 immunology Signal Transduction |
| Zdroj: | Immunology |
| ISSN: | 1365-2567 |
| Popis: | Of the thirteen Toll‐like receptors (TLRs) in mice, TLR2 has a unique ability of forming heterodimers with TLR1 and TLR6. Such associations lead to selective cellular signalling and cellular responses such as cytokine expression. One of the signalling intermediates is protein kinase C (PKC); of which, eight isoforms are expressed in macrophages. Leishmania—a protozoan parasite that resides and replicates in macrophages—selectively modulates PKC‐α, PKC‐β, PKC‐δ and PKC‐ζ isoforms in macrophages. As TLR2 plays significant roles in Leishmania infection, we examined whether these PKC isoforms play selective roles in TLR2 signalling and TLR2‐induced anti‐leishmanial functions. We observed that the TLR2 ligands—Pam(3)CSK(4) (TLR1/2), PGN (TLR2/2) and FSL (TLR2/6)—differentially phosphorylated and translocated PKC‐α, PKC‐β, PKC‐δ and PKC‐ζ isoforms to cell membrane in uninfected and L. major‐infected macrophages. The PKC isoform‐specific inhibitors differentially altered IL‐10 and IL‐12 expression, Th1 and Th2 responses and anti‐leishmanial effects in macrophages and in BALB/c mice. While PKC isoforms’ inhibitors had insignificant effects on the Pam3CSK4‐induced anti‐leishmanial functions, PGN‐induced pro‐leishmanial effects were enhanced by PKC‐(α + β) inhibitors, whereas PKC‐(δ + ζ) inhibitors enhanced the anti‐leishmanial effects of FSL. These results indicated that the ligand‐induced TLR2 dimerization triggered differential dose‐dependent and kinetic profiles of PKC isoform activation and that selective targeting of PKC isoforms using their respective inhibitors in combination significantly modulated TLR2‐induced anti‐leishmanial functions. To the best of our knowledge, this is the first demonstration of TLR2 dimer signalling through PKC isoforms and TLR2‐induced PKC isoform‐targeted anti‐leishmanial therapy. |
| Databáze: | OpenAIRE |
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