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.
Jensen
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Department of Pharmacology, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Whitehead
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D000210:Acute-Phase Reaction / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D005938:Glucocorticoids; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D014157:Transcription Factors