期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 45, 期 1, 页码 101-112出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201444818
关键词
Chemokines; Chemotaxis; DCs; Monocytes; Serum amyloid A
类别
资金
- Concerted Research Actions (G.O.A.) of the Regional Government of Flanders
- Fund for Scientific Research of Flanders (F.W.O.-Vlaanderen)
- Interuniversity Attraction Poles Program Belgian Science Policy [P7/40]
- Hercules foundation of the Flemish government [AKUL/11/31]
Serum amyloid A (SAA) is an acute phase protein that is upregulated in inflammatory diseases and chemoattracts monocytes, lymphocytes, and granulocytes via its G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPRL1/FPR2). Here, we demonstrated that the SAA1 isoform also chemoattracts monocyte-derived immature dendritic cells (DCs) in the Boyden and -slide chemotaxis assay and that its chemotactic activity for monocytes and DCs was indirectly mediated via rapid chemokine induction. Indeed, SAA1 induced significant amounts (5 ng/mL) of macrophage inflammatory protein-1/CC chemokine ligand 3 (MIP-1/CCL3) and interleukin-8/CXC chemokine ligand 8 (IL-8/CXCL8) in monocytes and DCs in a dose-dependent manner within 3 h. However, SAA1 also directly activated monocytes and DCs for signaling and chemotaxis without chemokine interference. SAA1-induced monocyte migration was nevertheless significantly prevented (60-80% inhibition) in the constant presence of desensitizing exogenous MIP-1/CCL3, neutralizing anti-MIP-1/CCL3 antibody, or a combination of CC chemokine receptor 1 (CCR1) and CCR5 antagonists, indicating that this endogenously produced CC chemokine was indirectly contributing to SAA1-mediated chemotaxis. Further, anti-IL-8/CXCL8 antibody neutralized SAA1-induced monocyte migration, suggesting that endogenous IL-8/CXCL8 acted in concert with MIP-1/CCL3. This explained why SAA1 failed to synergize with exogenously added MIP-1/CCL3 or stromal cell-derived factor-1 (SDF-1)/CXCL12 in monocyte and DC chemotaxis. In addition to direct leukocyte activation, SAA1 induces a chemotactic cascade mediated by expression of cooperating chemokines to prolong leukocyte recruitment to the inflammatory site.
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