Inflammation-responsive transcription factor SAF-1 activity is linked to the development of amyloid A amyloidosis

J Immunol. 2006 Aug 15;177(4):2601-9. doi: 10.4049/jimmunol.177.4.2601.

Abstract

Abundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman's disease. An inflammation-responsive transcription factor, SAF (for SAA activating factor), has been implicated in the sustained expression of amyloidogenic SAA under chronic inflammatory conditions. However, its role in the pathogenesis of AA amyloidosis has thus far remained obscure. In this paper we have shown that SAF-1, a major member of the SAF family, is abundantly present in human AA amyloidosis patients. To assess whether SAF-1 is directly linked to the pathogenesis of AA amyloidosis, we have developed a SAF-1 transgenic mouse model. SAF-1-overexpressing mice spontaneously developed AA amyloidosis at the age of 14 mo or older. Immunohistochemical analysis confirmed the nature of the amyloid deposits as an AA type derived from amyloidogenic SAA1. Furthermore, SAF-1 transgenic mice rapidly developed severe AA amyloidosis in response to azocasein injection, indicating increased susceptibility to inflammation. Also, during inflammation SAF-1 transgenic mice exhibited a prolonged acute phase response, leading to an extended period of SAA synthesis. Together, these results provide direct evidence that SAF-1 plays a key role in the development of AA amyloidosis, a consequence of chronic inflammation.

MeSH terms

  • Amyloidosis / chemically induced
  • Amyloidosis / genetics
  • Amyloidosis / immunology*
  • Amyloidosis / pathology*
  • Animals
  • Caseins / toxicity
  • Chronic Disease
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Humans
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology*
  • Kidney Diseases / chemically induced
  • Kidney Diseases / genetics
  • Kidney Diseases / immunology
  • Kidney Diseases / pathology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Serum Amyloid A Protein / biosynthesis
  • Serum Amyloid A Protein / genetics
  • Serum Amyloid A Protein / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • Caseins
  • DNA-Binding Proteins
  • Inflammation Mediators
  • Serum Amyloid A Protein
  • Transcription Factors
  • azocasein
  • c-MYC-associated zinc finger protein