Submitted to: International Immunopharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2003
Publication Date: 12/1/2003
Citation: Farnell, M.B., He, H., Genovese, K.J., Kogut, M.H. 2003. Pharmacological analysis of signal transduction pathways required for oxidative burst in chicken heterophils stimulated by a toll-like receptor 2 agonist. International Immunopharmacology. 3:1677-1684. Interpretive Summary: Baby chicks are very vulnerable to bacterial infections during the first two weeks of life. Chickens have cells that fight these infections. One group of these cells, called heterophils, is especially good at killing bacteria in baby chicks. Chicken heterophils have been previously shown to recognize bacteria by a group of receptors called Toll-like receptors. These Toll-like receptors tell the heterophil what to do by initiating a cascade of chemical interactions within the cell. The objective of this study was to identify some of these chemical interactions in chicken heterophils. We found that different chemical patterns are seen in heterophils when they are stimulated with different bacteria thru Toll-like receptors. These studies are important to the pharmaceutical industry because if these chemical patterns can be manipulated they may be able to protect baby chicks from infection.
Technical Abstract: Toll-like receptors (TLRs) play an important role in the innate immune response of avian heterophils. We previously used the pharmacological inhibitors genistein, verapamil, chelerythrine, and pertussis toxin to investigate the upstream signaling events involved in TLR2-mediated oxidative burst in chicken heterophils. Only chelerythrine, a protein kinase C inhibitor, was found to significantly inhibit oxidative burst stimulated by the TLR2 agonist lipoteichoic acid (LTA). In the present study, we used selective pharmacological inhibitors to investigate the roles of phosphatidylinositol-3'-kinase (P13-K), phospholipase C (PLC), calcium dependent protein kinase C (PKC), extra-cellular signal regulated kinase (ERK), and nuclear translocation factor KB (NFKB) on TLR2-mediated oxidative burst. U-73122 (a PLC inhibitor), wortmannin (a P13-K inhibitor), PD 98059 (an ERK inhibitor), Go 6976 (a PKC inhibitor) and Bay 11-7082 (a NFKB inhibitor) significantly decreased LTA-stimulated oxidative burst in heterophils by 77, 30, 36, 78, and 61%, respectively. Activated TLR2 utilizes P13-K, PLC, PKC, ERK, and NFKB as signaling factors that mediate the oxidative burst of chicken heterophils.