Regulation of A1PI expression in monocytes and macrophages: potential role in anti-pathogen responses

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	FDA/CBER	INFECTDIS-15

* FARE Award Winner

Authors

• Y WANG
• Y HE
• D SCOTT
• J REED

Abstract

Alpha-1 Proteinase Inhibitor (A1PI) is a serine protease inhibitor which covalently binds and blocks neutrophil elastase activity. Some patients with congenital A1PI deficiency display early-onset emphysema and reduced life expectancy. The contributions of A1PI to lung homeostasis are incompletely described. Monocytes and macrophages can express A1PI. We hypothesized that A1PI modifies inflammatory responses of macrophages in an autocrine and/or paracrine manner. Primary monocytes from adults and infants, and monocytic U937 cells, secrete A1PI at high levels. However, A1PI protein is also expressed in a non-secreted form by other monocytic cell lines (THP-1, MM6, 28SC). Secretion of A1PI by monocytic cell lines was inversely correlated with TLR ligand-stimulated responses such as TNF-a and IL-1b release and apoptosis. Mechanisms by which A1PI dampens innate immune signals are currently under investigation. Using immunohistochemistry, we demonstrated that A1PI was strongly detected and colocalized with CD68 positive cells in patients with cystic fibrosis, and in infants with primary RSV or influenza bronchiolitis. Together our data suggest point to a novel role for A1PI in regulating anti-pathogen responses in monocytes and macrophages. Deficient macrophage responses to respiratory insults may contribute to emphysema in patients with A1PI deficiency.

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