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      Serum Amyloid A Protein Concentration in Blood is Influenced by Genetic Differences in the Cheetah ( Acinonyx jubatus)

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          Abstract

          Systemic amyloid A (AA) amyloidosis is a major cause of morbidity and mortality among captive cheetahs. The self-aggregating AA protein responsible for this disease is a byproduct of serum amyloid A (SAA) protein degradation. Transcriptional induction of the SAA1 gene is dependent on both C/EBPβ and NF-κB cis-acting elements within the promoter region. In cheetahs, 2 alleles exist for a single guanine nucleotide deletion in the putative NF-κB binding site. In this study, a novel genotyping assay was developed to screen for the alleles. The results show that the SAA1A −97delG allele is associated with decreased SAA protein concentrations in the serum of captive cheetahs ( n = 58), suggesting genetic differences at this locus may be affecting AA amyloidosis prevalence. However, there was no significant difference in the frequency of the SAA1A −97delG allele between individuals confirmed AA amyloidosis positive versus AA amyloidosis negative at the time of necropsy ( n = 48). Thus, even though there is evidence that having more copies of the SAA1A −97delG allele results in a potentially protective decrease in serum concentrations of SAA protein in captive cheetahs, genotype is not associated with this disease within the North American population. These results suggest that other factors are playing a more significant role in the pathogenesis of AA amyloidosis among captive cheetahs.

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          Most cited references31

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          The acute phase response.

          Adult mammals respond to tissue damage by implementing the acute phase response, which comprises a series of specific physiological reactions. This review outlines the principal cellular and molecular mechanisms that control initiation of the tissue response at the site of injury, the recruitment of the systemic defense mechanisms, the acute phase response of the liver and the resolution of the acute phase response.
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            Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation.

            Nuclear factor kappa B (NF-kappa B) is a critical regulator of several genes which are involved in immune and inflammation responses. NF-kappa B, consisting of a 50-kDa protein (p50) and a 65-kDa protein (p65), is bound to a cytoplasmic retention protein called I kappa B. Stimulation of cells with a variety of inducers, including cytokines such as tumor necrosis factor and interleukin-1, leads to the activation and the translocation of p50/65 NF-kappa B into the nucleus. However, the in vivo mechanism of the activation process remains unknown. Here, we provide the first evidence that the in vivo mechanism of NF-kappa B activation is through the phosphorylation and subsequent loss of its inhibitor, I kappa B alpha. We also show that both I kappa B alpha loss and NF-kappa B activation are inhibited in the presence of antioxidants, demonstrating that the loss of I kappa B alpha is a prerequisite for NF-kappa B activation. Finally, we demonstrate that I kappa B alpha is rapidly resynthesized after loss, indicating that an autoregulatory mechanism is involved in the regulation of NF-kappa B function. We propose a mechanism for the activation of NF-kappa B through the modification and loss of I kappa B alpha, thereby establishing its role as a mediator of NF-kappa B activation.
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              Regulation of serum amyloid A protein expression during the acute-phase response.

              The acute-phase (AP) serum amyloid A proteins (A-SAA) are multifunctional apolipoproteins which are involved in cholesterol transport and metabolism, and in modulating numerous immunological responses during inflammation and the AP response to infection, trauma or stress. During the AP response the hepatic biosynthesis of A-SAA is up-regulated by pro-inflammatory cytokines, and circulating concentrations can increase by up to 1000-fold. Chronically elevated A-SAA concentrations are a prerequisite for the pathogenesis of secondary amyloidosis, a progressive and fatal disease characterized by the deposition in major organs of insoluble plaques composed principally of proteolytically cleaved A-SAA, and may also contribute to physiological processes that lead to atherosclerosis. There is therefore a requirement for both positive and negative control mechanisms that permit the rapid induction of A-SAA expression until it has fulfilled its host-protective function(s) and subsequently ensure that its expression can be rapidly returned to baseline. These mechanisms include modulation of promoter activity involving, for example, the inducer nuclear factor kappaB (NF-kappaB) and its inhibitor IkappaB, up-regulatory transcription factors of the nuclear factor for interleukin-6 (NF-IL6) family and transcriptional repressors such as yin and yang 1 (YY1). Post-transcriptional modulation involving changes in mRNA stability and translation efficiency permit further up- and down-regulatory control of A-SAA protein synthesis to be achieved. In the later stages of the AP response, A-SAA expression is effectively down-regulated via the increased production of cytokine antagonists such as the interleukin-1 receptor antagonist (IL-1Ra) and of soluble cytokine receptors, resulting in less signal transduction driven by pro-inflammatory cytokines.
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                Author and article information

                Journal
                J Hered
                J. Hered
                jhered
                Journal of Heredity
                Oxford University Press (US )
                0022-1503
                1465-7333
                March 2016
                19 November 2015
                01 March 2017
                : 107
                : 2
                : 115-121
                Affiliations
                [1 ]From the Animal Sciences Department , University of Maryland College Park , College Park, MD 20742, USA (Franklin); Center for Species Survival , Smithsonian Conservation Biology Institute , 1500 Remount Road, Front Royal, VA 22630, USA (Franklin and Crosier); Cheetah Conservation Fund , PO Box 1755, Otjiwarongo, Namibia (Schmidt-Küntzel and Marker); Life Technologies Conservation Genetics Laboratory , Cheetah Conservation Fund , PO Box 1755, Otjiwarongo, Namibia (Schmidt-Küntzel); University of Illinois Zoological Pathology Program , Maywood, IL 60153, USA (Terio).
                Author notes

                Address correspondence to Ashley D. Franklin at the address above, or e-mail: ashley.franklin@ 123456pdza.org .

                Corresponding editor: Elaine Ostrander.

                Article
                esv089
                10.1093/jhered/esv089
                5994965
                26585380
                b94943e4-a17d-4a6b-8256-5215875154c8
                © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 24 August 2015
                : 22 October 2015
                : 19 October 2015
                Page count
                Pages: 7
                Funding
                Funded by: NIH 10.13039/100000002
                Funded by: University of Maryland 10.13039/100008510
                Funded by: Cosmos Club Foundation 10.13039/100008544
                Funded by: Smithsonian Institution 10.13039/100000014
                Categories
                Original Articles

                Genetics
                acute phase response,amyloidosis,cheetah,genetic typing of insertion/deletion,serum amyloid a

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