TLR2 dimer-specific ligands selectively activate protein kinase C isoforms in Leishmania infection.

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-ß, 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-Pam3 CSK4 (TLR1/2), PGN (TLR2/2) and FSL (TLR2/6)-differentially phosphorylated and translocated PKC-α, PKC-ß, 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 + ß) inhibitors, whereas PKC-(δ + Î¶) 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.

An Overview of Seasonal Changes in Oxidative Stress and Antioxidant Defence Parameters in Some Invertebrate and Vertebrate Species.

Antioxidant defence system, a highly conserved biochemical mechanism, protects organisms from harmful effects of reactive oxygen species (ROS), a by-product of metabolism. Both invertebrates and vertebrates are unable to modify environmental physical factors such as photoperiod, temperature, salinity, humidity, oxygen content, and food availability as per their requirement. Therefore, they have evolved mechanisms to modulate their metabolic pathways to cope their physiology with changing environmental challenges for survival. Antioxidant defences are one of such biochemical mechanisms. At low concentration, ROS regulates several physiological processes, whereas at higher concentration they are toxic to organisms because they impair cellular functions by oxidizing biomolecules. Seasonal changes in antioxidant defences make species able to maintain their correct ROS titre to take various physiological functions such as hibernation, aestivation, migration, and reproduction against changing environmental physical parameters. In this paper, we have compiled information available in the literature on seasonal variation in antioxidant defence system in various species of invertebrates and vertebrates. The primary objective was to understand the relationship between varied biological phenomena seen in different animal species and conserved antioxidant defence system with respect to seasons.