TY - JOUR T1 - Alpha-1-antitrypsin regulates IL-8 release and CXCR2 expression in human neutrophils JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P2487 AU - Nupur Aggarwal AU - Jan Hegermann AU - Veronica Grau AU - Matthias Ochs AU - Tobias Welte AU - Sabina Janciauskiene Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P2487.abstract N2 - The modulation of the neutrophil CXC chemokine receptor-2 (CXCR2) is an important mechanism controlling neutrophil responsiveness. The expression of CXCR2 is rapidly down-modulated by lipopolysaccharide (LPS) via tyrosine kinase-dependent mechanism whereas IL-8 accounts for the similar down-modulation of surface CXCR2 expression through rapid receptor internalization. Acute phase protein, α1-antitrypsin (A1AT), is a know regulator of neutrophil responses to LPS, however AAT's effect on the CXCR2 expression has not been investigated. Priming of human neutrophils with LPS (10ng/3x106 cells) caused a time-dependent decrease of surface CXCR2 levels and reduction in mRNA CXCR2 (80%, p=0.027) by 4 hours. At 1h, A1AT (1mg/3x106cells) enhanced whereas at 4 h abolished effect of LPS on CXCR2 expression. Similarly, when compared to IL-8 (50 ng/3x106 cells) primed cells, addition of AAT caused an enhanced internalization (for up to 1h) and a subsequent re-expression (at 4h) of the surface CXCR2 without effecting mRNA of CXCR2. Remarkably, within a short-term (1h) A1AT enters into the neutrophil, induces transient ERK1/2 activation and localizes into plasma membranes, cytosol and secretary vesicles pushing out IL-8 from these compartments. Pretreatment with U0126, a highly specific MEK1/2 inhibitor, abolished A1AT ability to induce ERK1/2 activation and IL-8 release, and attenuated effect of A1AT on CXCR2 expression in LPS or IL-8-primed neutrophils. Our data show that A1AT modulates surface CXCR2 expression via activation of ERK1/2 pathway and concomitant modulation of IL-8 release. These findings help us to understand the therapeutic role of A1AT in combating neutrophil mediated inflammation. ER -