Roles for phosphoinositide 3-kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing.
B lymphocyte chemokine receptors signal to downstream effectors by activating heterotrimeric G proteins. However, many of these effectors remain unknown and the known ones often have ill-defined roles in B cell trafficking. Here we report that pharmacological inhibitors of phosphoinositide 3-kinases (wortmannin, WMN), Bruton's tyrosine kinase (LFM-A13), and Jun kinases (SP600125) all significantly impair CXCL12-induced mouse B cell chemotaxis and that of a human B lymphoma cell line. Examination of two CXCR4-induced signaling pathways revealed that LFM-A13 and WMN blocked Akt activation, while SP600125 and WMN blocked JNK activation. Each of the inhibitors impaired the homing of transferred B cells to peripheral lymph nodes. Intravital imaging of control and inhibitor-treated mouse B cells in the inguinal lymph node high endothelial venules (HEV) demonstrated a 17%, 35%, and 60% reduction in the number of firmly adherent B cells with LFM-A13, SP600125, and WMN, respectively. These results implicate chemokine receptor mediated activation of phosphoinositide 3-kinases in the firm adhesion of mouse B cells within peripheral lymph node HEV, while Bruton's tyrosine kinase and JNK activation are less important and more likely needed during B cell transmigration through the endothelium and/or trafficking into the lymph node parenchyma.
Ortolano
Saida
S
B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hwang
Il-Young
IY
Han
Sang-Bae
SB
Kehrl
John H
JH
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000077191:Wortmannin
D000577:Amides; D000730:Androstadienes; D000873:Anthracenes; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C118451:LFM A13; D009570:Nitriles; C432165:pyrazolanthrone; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium; D000077191:Wortmannin