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Blood, 8 January 2009, Vol. 113, No. 2, pp. 429-437. Prepublished online as a Blood First Edition Paper on October 24, 2008; DOI 10.1182/blood-2008-03-139923.
PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 21 Department of Pharmacology, University of Illinois College of Medicine, Chicago
The acute-phase protein serum amyloid A (SAA) is commonly considered a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principal cytokine-regulating granulocytosis. This effect of SAA is dependent on Toll-like receptor 2 (TLR2). Our data demonstrate that, in mouse macrophages, both G-CSF mRNA and protein were significantly increased after SAA stimulation. The induction of G-CSF was blocked by an anti-TLR2 antibody and markedly decreased in the TLR2-deficient macrophages. SAA stimulation results in the activation of nuclear factor–
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B and binding activity to the CK-1 element of the G-CSF promoter region. In vitro reconstitution experiments also support that TLR2 mediates SAA-induced G-CSF expression. In addition, SAA-induced secretion of G-CSF was sensitive to heat and proteinase K treatment, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Finally, our in vivo studies confirmed that SAA treatment results in a significant increase in plasma G-CSF and neutrophilia, whereas these responses are ablated in G-CSF– or TLR2-deficient mice.