Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen.
Signal transduction initiated by B cell Ag receptor (BCR) cross-linking plays an important role in the development and activation of B cells. Therefore, considerable effort has gone into determining the biochemical signaling events initiated by the BCR and delineating which events participate in specific biological responses to Ag. We used two inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1 and MEK2, PD98059, and U0126, to assess the role the Ras-mitogen-activated protein kinase pathway plays in several BCR-induced responses. PD98059 or U0126 treatment substantially inhibited the BCR-induced activation of the extracellular signal-regulated kinase (ERK) forms of mitogen-activated protein kinase in the immature B cell line WEHI-231, in immature splenic B cells, and in mature splenic B cells. However, MEK-ERK inhibition did not block BCR-induced growth arrest or apoptosis of WEHI-231 cells or apoptosis of immature splenic B cells, indicating that the MEK-ERK pathway is not required for these events. In contrast, PD98059 and U0126 treatment did inhibit the up-regulation of specific BCR-induced proteins, including the transcription factor Egr-1 in WEHI-231 and mature splenic B cells, and the CD44 adhesion molecule and CD69 activation marker in mature splenic B cells. Moreover, both inhibitors suppressed BCR-induced proliferation of mature splenic B cells, in the absence and in the presence of IL-4. Therefore, activation of the MEK-ERK pathway is necessary for a subset of B cell responses to Ag.
Richards
J D
JD
Department of Microbiology and Immunology, G. W. Hooper Foundation, University of California, San Francisco, CA 94143, USA.
Davé
S H
SH
Chou
C H
CH
Mamchak
A A
AA
DeFranco
A L
AL
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D017874:Immediate-Early Proteins; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000099192:CD69 Antigens
D000941:Antigens; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002070:Butadienes; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D018960:Hyaluronan Receptors; D017874:Immediate-Early Proteins; D037181:Lectins, C-Type; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D000099192:CD69 Antigens; C486109:Egr1 protein, mouse; C113580:U 0126; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one