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Title:   Author  item
                                            Kogut, Michael

                                                         - *Mike*item
                                            Genovese, Kenneth

                                                         - *Ken*item
                                            He, Louis
  Submitted to: Molecular Immunology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/24/2006
                                    Publication  Date: 10/12/2006
                                    Citation: Kogut, M.H., Genovese, K.J., He, H. 2006. Flagellin and lipopolysaccharide stimulate the MEK-ERK signaling pathway in chicken heterophils through differential activation of the small GTPases, Ras and Rap1. Molecular Immunology. 44:1729-1736.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.  We do not know the reason for this problem.  The objective of this experiment was to look at a specific white blood cell of the chicken called the heterophil and determine how the cells’ internal machinery is controlled.  We found that different components of the cells’ machinery are controlled by totally different chemical processes that are independent of each other.  Therefore, the cell can control different components of its internal machinery independently and at different times.  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 cells of the immune system without affecting other parts.  Thus, it is possible to help the immune response without causing damage to the chick.  It may be possible to develop new drugs that can increase the chick’s immune system and provide protection against infections such as Salmonella.
                                Technical Abstract: The TLR agonists, flagellin (FLG) and lipopolysaccharide (LPS) stimulate functional activation and cytokine gene expression via the extracellular signal regulated kinase 1/2 (ERK 1/2) MAP kinase cascade. However, the upstream mechanisms of these signaling events remain unknown.  In mammals, the small GTP-binding protein Ras mediates ERK 1/2 activation through activation of downstream effectors Raf-1-MEK 1/2-ERK 1/2 in response to a variety of stimuli.  It is not clear whether this classic Ras cascade plays a role in TLR signaling in avian cells.  In the present study, we investigated the role of Ras in FLG- and LPS-mediated signaling in ERK activation in chicken heterophils.  Treatment of heterophils with LPS caused a rapid (within 5 min) activation of Ras-GTP.  The role of Ras activation in LPS-induced stimulation of ERK 1/2 was corroborated when the specific Ras inhibitor, FTI-277, inhibited ERK 1/2 activation.  The classic Ras-mediated pathway of ERK 1/2 activation by LPS was confirmed when the specific Raf-1 inhibitor, GW 5074, and the MEK 1/2 inhibitor, U0126, both reduced ERK activation by 51-60%.  Of more interest was that treatment of the heterophils with FLG did not activate Ras-GTP.  Likewise, neither FTI-277 nor GW 5074 had any effect on FLG-mediated activation of ERK 1/2.  Another small GTPase, Rap1, has been shown to play a role in mammalian neutrophil function.  Using a Rap1-GTP pull-down assay, we found that FLG stimulation, but not LPS, of avian heterophils induced a rapid and transient Rap1 activation.  Rap1 has been shown to activate the ERK 1/2 via a different Raf family member B-Raf whose downstream effector is MEK1/2.  We show here that FLG stimulation of heterophils induces the phosphorylation of B-Raf.  The FLG induction of the Rap-1'B-Raf'MEK 1/2'ERK 1/2 cascade was confirmed by the reduction of ERK 1/2 activation by the specific B-Raf inhibitor (GGTI-298) and U0126.  The results demonstrate that for the first time that the small GTPase Ras family is involved in TLR signaling of avian heterophils with the TLR agonists LPS (Ras) and FLG (Rap1) inducing differential signaling cascades to activate the downstream ERK MAP kinase.


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