Serum amyloid a regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2

Edward Chen, Zhimin Song, Matthew H. Willett, Shannon Heine, Rex C. Yung, Mark Chang Hwa Liu, Steve D. Groshong, Ying Zhang, Rubin M. Tuder, David Moller

Research output: Contribution to journalArticle

Abstract

Rationale: The critical innate immune mechanisms that regulate granulomatous inflammation in sarcoidosis are unknown. Because the granuloma-inducing component of sarcoidosis tissues has physicochemical properties similar to those of amyloid fibrils, we hypothesized that host proteins capable of forming poorly soluble aggregates or amyloid regulate inflammation in sarcoidosis. Objectives: To determine the role of the amyloid precursor protein, serum amyloid A, as an innate regulator of granulomatous inflammation in sarcoidosis. Methods: Serum amyloid A expression was determined by immunohistochemistry in sarcoidosis and control tissues and by ELISA. The effect of serum amyloid A on nuclear factor (NF)-κB induction, cytokine expression, and Toll-like receptor-2 stimulation was determined with transformed human cell lines and bronchoalveolar lavage cells from patients with sarcoidosis. The effects of serum amyloid A on regulating helper T cell type 1 (Th1) granulomatous inflammation were determined in experimental models of sarcoidosis, using Mycobacterium tuberculosis catalase-peroxidase. Measurements and Main Results: We found that the intensity of expression and distribution of serum amyloid A within sarcoidosis granulomas was unlike that in many other granulomatous diseases. Serum amyloid A localized to macrophages and giant cells within sarcoidosis granulomas but correlated with CD3+ lymphocytes, linking expression to local Th1 responses. Serumamyloid A activated NF-κB in Toll-like receptor-2-expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-g, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2. Conclusions: Serum amyloid A is a constituent and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2, providing a mechanism for chronic disease and new therapeutic targets.

Original languageEnglish (US)
Pages (from-to)360-373
Number of pages14
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume181
Issue number4
DOIs
StatePublished - Feb 15 2010

Fingerprint

Toll-Like Receptor 2
Sarcoidosis
Amyloid
Serum Amyloid A Protein
Inflammation
Serum
Granuloma
Interleukin-10
Tumor Necrosis Factor-alpha
Transformed Cell Line
Th1 Cells
Interleukin-18
Amyloid beta-Protein Precursor
Bronchoalveolar Lavage
Giant Cells
Mycobacterium tuberculosis
Catalase
Peroxidase
Chronic Disease
Theoretical Models

Keywords

  • Cytokines
  • Granuloma
  • Innate immunity
  • Sarcoidosis
  • Serum amyloid A

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Serum amyloid a regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2. / Chen, Edward; Song, Zhimin; Willett, Matthew H.; Heine, Shannon; Yung, Rex C.; Liu, Mark Chang Hwa; Groshong, Steve D.; Zhang, Ying; Tuder, Rubin M.; Moller, David.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 181, No. 4, 15.02.2010, p. 360-373.

Research output: Contribution to journalArticle

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AU - Yung, Rex C.

AU - Liu, Mark Chang Hwa

AU - Groshong, Steve D.

AU - Zhang, Ying

AU - Tuder, Rubin M.

AU - Moller, David

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