IFN{alpha} enhances human B-cell chemotaxis by modulating ligand-induced chemokine receptor signaling and internalization.
In this study, we show that IFNalpha increases the chemotaxis of human B cells to CCL20, CCL21 and CXCL12 in a dose- and time-dependent manner. The effect was maximal with 2000 IU ml(-1) IFNalpha. It peaked at 24 h and decreased thereafter. At 24 h, IFNalpha had increased B-cell chemotaxis to CCL20 by 20 +/- 6.2% (n = 9, P < 0.002), to CCL21 by 20 +/- 8.5% (n = 14, P < 0.0001) and to CXCL12 by 16.3 +/- 4.2% (n = 12, P < 0.003) without changing CCR6, CCR7 or CXCR4 expression. IFNalpha enhanced the migration of memory B cells to CCL20, CCL21 and CXCL12 2.6-fold more strongly than that of naive B cells. The triggering of chemokine receptors by their ligands resulted in the activation of phosphatidylinositide-3 kinase (PI3K)/protein kinase B (PKB), inhibitory NF-kappaB (IkappaBalpha) RhoA and extracellular signal-regulated protein kinase 1/2 (ERK1/2). All these effectors except ERK1/2 are crucial for B-cell chemotaxis. IFNalpha modulated the requirements for B-cell chemotaxis, which became dependent on ERK1/2, more dependent on PI3K, RhoA and nuclear factor-kappaB but less dependent on Gbetagamma and phospholipase C activation. IFNalpha also decreased ligand-induced chemokine receptor internalization in a manner dependent on PI3K/AKT and RhoA but not on IkappaBalpha and ERK1/2. Our data characterize chemokine receptor signaling in human B cells and clarify the relevance of downstream pathways in B-cell chemotaxis and chemokine receptor internalization. They also suggest that non-class I PI3K are involved in B-cell chemotaxis.
Badr
Gamal
G
Institut National de la Santé et de la Recherche Medicale U 131, Institut Paris-Sud sur les Cytokines, 32 rue des Carnets, 92 140, Clamart, France.
Borhis
Gwenoline
G
Treton
Dominique
D
Richard
Yolande
Y
D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology*; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D007155:Immunologic Factors; D016898:Interferon-alpha; D008024:Ligands; D016328:NF-kappa B; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases; D020742:rhoA GTP-Binding Protein