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A subset of B lymphocytes present primarily in the peritoneal and pleural cavities is defined by the expression of CD5 and is elevated in autoimmune diseases. Upon signaling through membrane immunoglobulin M (mIgM), splenic B lymphocytes (B-2) proliferate, whereas peritoneal B cells (B-1) undergo apoptosis. However, in CD5-deficient mice, B-1 cells responded to mIgM crosslinking by developing a resistance to apoptosis and entering the cell cycle. In wild-type B-1 cells, prevention of association between CD5 and mIgM rescued their growth response to mIgM crosslinking. Thus the B cell receptor-mediated signaling is negatively regulated by CD5 in normal B-1 cells.

IntroductionJun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) is one of the 3 major members of the mitogenactivated protein kinase (MAPK) superfamily; the others are extracellular signal-regulated kinase (ERK) and the p38 MAP kinase. JNK is activated in response to certain growth factors or stresses such as ultraviolet (UV) radiation. Stress-induced JNK activation often leads to cell death through activation of the mitochondrial apoptotic pathway in many cell types including neuronal cells, prostate cancer cells, and fibroblasts. [1][2][3][4] On the contrary, it has been shown recently that JNK can promote survival of BCR/ABL-transformed leukemic cells. 5 Triggering the JNK pathway in vitro with a BCR-ABL tyrosine kinase led to a dramatic increase in B-cell transformation. Moreover, it was shown that JNK is required for interleukin-3 (IL-3)-mediated cell survival through its ability to phosphorylate and inactive the proapoptotic Bcl-2 family protein BAD. 6 JNK protein kinases are coded for by 3 genes, Jnk1, Jnk2, and Jnk3. Jnk1 and Jnk2 are the more widely expressed isoforms of JNK. Jnk3 is limited in expression, restricted primarily to the brain, heart, and testis. JNK is activated by upstream MAPK kinases, Activated JNK phosphorylates and activates its major substrate c-jun as well as several other transcription factors and proteins required for cell survival, proliferation, transformation, and cell death. 10 The dual role of JNK in both apoptotic and survival signaling pathways indicates that the functional role of JNK is complex. The biologic outcome of JNK activation depends upon the cellular context, time course of activation, and the balance between the ability of JNK to signal both apoptosis and cell survival. The complexity of the cellular response to JNK activation can be illustrated by the diverse actions of a proinflammatory cytokine tumor necrosis factor alpha (TNF-␣). Sustained activation of JNK correlates with TNF-induced apoptosis of rat mesangial cells. 11 On the other hand, JNK1 and JNK2 double knock-out fibroblasts are more sensitive to TNF-induced apoptosis compared with wild-type fibroblasts, suggesting a prosurvival role for JNK signaling in these cells. 12 Recent findings that MKK7 (an upstream activator of JNK) knock-out hepatocytes fail to proliferate and that mouse embryo fibroblasts that lack MKK7 undergo cellular senescence and G 2 /M growth arrest further support a role for JNK in cell-cycle progression. 13 The role of JNK during primary B-lymphocyte growth responses still awaits complete illumination. Signaling through CD72, CD40, or B-cell receptor (BCR) ligation induces activation of MAP kinases, such as JNK, in primary splenic B cells. [14][15][16] However, no defect in BCR-or CD72-induced proliferation is observed in B cells from JNK1 Ϫ/Ϫ or JNK2 Ϫ/Ϫ mice. 14 This is probably due to a redundancy of function between the 2 isoforms, as JNK1 and JNK2 double knock outs exhibit embryonic lethality. 17 In T cells, JNK2 is required for the differentiatio...

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