Inhibition of the MEK/ERK Signaling Pathway Blocks a Subset of B Cell Responses to Antigen

Abstract

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.

B Cell Receptor (BCR) Cross-Talk: IL-4 Creates an Alternate Pathway for BCR-Induced ERK Activation That Is Phosphatidylinositol 3-Kinase Independent

“…BCR-induced MEK phosphorylation was completely blocked by U0126, and when MEK activation was blocked with U0126, anti-Ig-induced ERK phosphorylation was inhibited in B cells, in keeping with previous work (38). Similarly, antiIg-induced ERK phosphorylation was inhibited by U0126 in IL-4-treated B cells (Fig.…”

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

“…In normal B cells, B cell receptor engagement results in activation of STAT5 (Karras et al, 1996) and mitogen activated protein kinases (MAPK; Richards et al, 2001), which induce survival and proliferation, respectively. Likewise, B cell receptor engagement induced tyrosine phosphorylation of STAT5 and MAPK1 in two SLP65-deficient and one SLP65-expressing B cell lymphoma cell lines (Figure 4).…”

Transgenic Overexpression of G5PR That Is Normally Augmented in Centrocytes Impairs the Enrichment of High-Affinity Antigen-Specific B Cells, Increases Peritoneal B-1a Cells, and Induces Autoimmunity in Aged Female Mice

“…BCR stimulation induces either B cell proliferation or activationinduced cell death (AICD) through various BCR-mediated signaling pathways, including levels of intracellular Ca 2+ mobilization and activation of MAPKs and NF-kB, which are regulated by the phosphorylation status of various signaling molecules (9)(10)(11)(12). In BCR-mediated MAPK signaling, ERK is involved in cell proliferation (13,14), and JNK and p38 are involved in stress response and cell death (15)(16)(17). Many studies have suggested that B cell selection is attributable to a balanced regulation of activation strengths between cell survival and apoptotic signals (18)(19)(20)(21).…”