Is the serum amyloid A we use really serum amyloid A? Comment on the article by Connolly et al

Brand, Ben van den; Waterborg, Claire E J; Berg, W. van den; Loo, Faj van de

doi:10.1002/art.37737

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…A similar finding was made in another study (van den Brand et al, 2013). Together, these results suggest the possibility that the chimeric rhSAA may have acquired additional cytokine-inducing activity because of the altered amino acid sequence.…”

Section: Major Functions Of Human Saa1supporting

confidence: 91%

Serum amyloid A1: Structure, function and gene polymorphism

Sun

2016

Gene

164

134

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Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1 – SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

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Section: Major Functions Of Human Saa1supporting

confidence: 91%

Serum amyloid A1: Structure, function and gene polymorphism

Sun

2016

Gene

164

134

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“…In most studies, a recombinant SAA was used. Christenson et al [242] and van den Brand et al [243] directly compared the recombinant SAA1α (rSAA1α) and the recombinant hybrid between SAA1α and SAA2β (rSAA) for their chemokine inducing capacity. More CXCL8 was induced when stimulating synovial fibroblasts or neutrophils with rSAA than with rSAA1α.…”

Section: Remarks and Conclusionmentioning

confidence: 99%

Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults

Buck¹,

Gouwy²,

Wang³

et al. 2016

CMC

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Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100-fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (> 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.

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“…Nevertheless, an effect of contaminating LPS cannot be excluded, considering that TLR4 is one of the SAA receptors [64]. Of note, rhSAA1, prepared by the same manufacturer, has very low biologic activity in some of the functional assays [57], suggesting that it is possible to minimize LPS contamination in rSAA preparations to levels that do not affect significantly evaluation of SAA in functional assays. Studies that use 1 or more of these controls have shown that rhSAA still possesses biologic activities in the induction of cytokines and chemotaxis [25,28,31,43], the latter being less likely affected by LPS contamination as a result of the use of a G protein-coupled receptor, FPR2.…”

Section: Potential Involvement Of Saa In Inflammation and Unresolved mentioning

confidence: 99%

“…The exact reason for substituting these amino acids is unclear, but the resulting rhSAA becomes a hybrid of SAA1 and SAA2. In a letter to the editor of Arthritis & Rheumatism, van den Brand et al [57] compared this rhSAA hybrid with SAA1, which is also an E. coli-produced recombinant protein from the same commercial source. Their results indicate that the rSAA1 is much less effective in the induction of IL-8 transcripts and NF-kB activation.…”

Section: Potential Involvement Of Saa In Inflammation and Unresolved mentioning

confidence: 99%

Emerging functions of serum amyloid A in inflammation

Sun

2015

Journal of Leukocyte Biology

244

251

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SAA is a major acute-phase protein produced in large quantity during APR. The rise of SAA concentration in blood circulation during APR has been a clinical marker for active inflammation. In the past decade, research has been conducted to determine whether SAA plays an active role during inflammation and if so, how it influences the course of inflammation. These efforts have led to the discovery of cytokine-like activities of rhSAA, which is commercially available and widely used in most of the published studies. SAA activates multiple receptors, including the FPR2, the TLRs TLR2 and TLR4, the scavenger receptor SR-BI, and the ATP receptor P2X7. More recent studies have shown that SAA not only activates transcription factors, such as NF-κB, but also plays a role in epigenetic regulation through a MyD88-IRF4-Jmjd3 pathway. It is postulated that the activation of these pathways leads to induced expression of proinflammatory factors and a subset of proteins expressed by the M2 macrophages. These functional properties set SAA apart from well-characterized inflammatory factors, such as LPS and TNF-α, suggesting that it may play a homeostatic role during the course of inflammation. Ongoing and future studies are directed to addressing unresolved issues, including the difference between rSAA and native SAA isoforms and the exact functions of SAA in physiologic and pathologic settings.

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Is the serum amyloid A we use really serum amyloid A? Comment on the article by Connolly et al

Cited by 11 publications

References 29 publications

Serum amyloid A1: Structure, function and gene polymorphism

Serum amyloid A1: Structure, function and gene polymorphism

Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults

Emerging functions of serum amyloid A in inflammation

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