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Submitted to: Veterinary Immunology and Immunopathology
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 8/1/2005 Publication Date: 10/20/2006 Citation: Crippen, T.L. 2006. The selective inhibition of nitric oxide production in the avian macrophage cell line HD11. Veterinary Immunology and Immunopathology. 109:127-137. Interpretive Summary: The production of nitric oxide is a major mechanism by which the body's immune system defends itself against bacterial invasion. The purpose of this study was to investigate how cells know when to produce nitric oxide for defense. We investigated this in a specific type of chicken immune cell, called macrophages. These macrophages were exposed to chemicals that inhibit particular factors involved in the passing of the defense signal from the cell surface to the cell nucleus after bacteria attaches to the cell. After interrupting the signal with a chemical inhibitor, if there was a decrease in the production of nitric oxide, it indicated that this particular factor was involved in the transmission of the signal to turn on nitric oxide production. We found that several of the factors that we inhibited were involved in this signaling process and these factors are also involved in the passing of the signal in mammalian systems. This shows that the signaling process in birds is similar to that in mammals. This information allows us to better manipulate the immune system of birds to help defend against bacterial infection in order to keep our poultry healthy and our food supply safe. Technical Abstract: The production of reactive nitrogen, nitric oxide (NO), has previously been demonstrated to be a major mechanism by which the innate immune system defends against microbial invasion. The purpose of this study was to investigate components of the upstream signal transduction pathway induced by bacterial and viral-like stimulation of NO for antimicrobial defense by chicken macrophages. We quantified the production of nitrite by chicken macrophages after exposure to selective pharmacological inhibitors of specific signal transduction components prior to stimulation by polyinosinic polycytidylic acid (poly I:C), formalin-fixed Enterococcus gallinarum (EG) or formalin-fixed Klebsiella pneumoniae (KP). The induction of many antimicrobial peptide genes is regulated by numerous components during the transduction of the signal from the cell surface to the cell nucleus where response genes are unregulated. Toll-like cell surface receptor activation often leads to sequential modulation of protein tyrosine kinases (PTK), mitogen activated protein kinases (MAPK), degradation of IkappaB (IkappaB) regulatory molecules which, in turn, release the nuclear factor-kappa B (NF-kappaB) family proteins for translocation in to the nucleus and subsequent gene transcription. We found that NO production induced by dsRNA or bacteria was reduced in a dose dependent manner by specific inhibitors of PTK, p38 MAPK, IkappaB, NF-kappaB, but not JAK3. |
