|Kogut, Michael - Mike|
Submitted to: Immunopharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/27/2002
Publication Date: N/A
Interpretive Summary: During the first week of life after hatching, the immune system of the baby chick is not very good at fighting bacterial infections such as Salmonella, and we do not know why. The objective of this experiment was to look at a specific white blood cell of the chicken--called the heterophil--and determine whether the cells' internal machinery are controlled by the same chemicals reactions. We found that the various parts of the cells' machinery are controlled by totally different chemical processes that are independent of each other. Therefore, the cell can control different parts of its internal machinery at different times without using other parts of the machinery. The results of this experiment are important to the pharmaceutical industry in the United States because it shows that we can stimulate different parts of the baby chick's immune system cells, without affecting other parts. Thus, it is possible to help the immune response without causing damage to the chick.
Technical Abstract: We have been investigating the upstream signaling events that precede degranulation following crosslinkage of Fc receptors on heterophils. In the present studies, we used selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipase C, phosphatidylinositol 3'-kinase, and the family of mitogen-activated protein nkinases (MAPK) on Fc-mediated heterophil degranulation. Inhibitors of the receptor-linked tyrosine kinases (the tryphostins AG 1478 and AG 1296) had no attenuating effects on the Fc receptor-mediated degranulation of chicken heterophils. Likewise, PP2, a selective inhibitor of the Src family of protein tyrosine kinases, had no inhibitory effects on degranulation. However, piceatannol, a selective inhibitor of Syk tyrosine kinase, significantly attenuated the effect of Fc receptor-mediated degranulation. Additionally, Fc-mediated degranulation was significantly attenuated by SB 203580, an inhibitor of p38 MAPK, but not by PD98059, an inhibitor of the extracellular signal-regulated kinase (ERK). An inhibitor of phospholipase C, U73122 and an inhibitor of phosphoinositol-3 kinase, LY294002 significantly decreased heterophil degranulation. These results suggest that the Fc receptors on chicken heterophils, like their counterparts on mammalian neutrophils, have no intrinsic tyrosine kinase activity, but probably mediate downstream events through activation of tyrosine-based activation motif (ITAM). Engaging Fc receptors on chicken heterophils activate a Syk to PLC to PI3-K to p38 MAPK signal transduction pathway that induces degranulation.