Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells.

Abstract

Apoptosis of the WEHI 231 immature B cell lymphoma line following membrane interaction with an antibody against the surface IgM chains (anti‐IgM) is preceded by dramatic changes in Nuclear Factor‐kappaB (NF‐kappaB)/ Rel binding activities. An early transient increase in NF‐kappaB/Rel binding is followed by a significant decrease in intensity below basal levels. Here we have explored the role of these changes in Rel‐related factors in B cell apoptosis. Treatment of WEH1 231 cells with N‐tosyl‐L‐phenylalanine chloromethyl ketone (TPCK), a protease inhibitor which prevents degradation of the inhibitor of NF‐kappaB (IkappaB)‐alpha, or with low doses of pyrrolidinedithiocarbamate (PDTC) selectively inhibited NF‐kappaB/Rel factor binding and induced apoptosis. Bcl‐XL expression protected WEHI 231 cells from apoptosis induced by these agents. Microinjection of WEHI 231 cells with either IkappaB‐alpha‐GST protein or a c‐Rel affinity‐purified antibody induced apoptosis. Ectopic c‐Rel expression ablated apoptosis induced by TPCK or anti‐IgM. Treatment of BALENLM 17 and A20 B lymphoma cells or normal murine splenic B lymphocytes with either TPCK or PDTC also resulted in apoptosis. These findings indicate that the drop in NF‐kappaB/Rel binding following anti‐IgM treatment activates apoptosis of WEHI 231 cells; furthermore, they implicate the NF‐kappaB/Rel family in control of apoptosis of normal and transformed B cells.

Interleukin‐13 and ‐4 induce death of activated microglia

“…Based on those reports and our present data, it may be that the antiactivation cytokines IL-13 and IL-4 inhibit the expression of certain self-defense-related genes induced by microglial activators, which in turn leads to microglial cell death. Another possible mechanism for IL-13-induced death of activated microglia is inhibition of NF-B, since NF-B is known as a cell survival factor and IL-13 inhibits activation of NF-B (Wu et al, 1996;Lentsch et al, 1997;Manna and Aggarwal, 1998). However, IL-13 seems to induce microglial cell death via different pathways than those involved in inhibition of microglial NO release.…”

NF-κB and the immune response

“…NF-kB activity is required for the maintenance of long-lived B and T cells. (Wu et al, 1996). Decreased NF-kB activity might then sensitize these cells to proapoptotic signals.…”

Current insights into the regulation of programmed cell death by NF-κB

“…In contrast, PCD via necrosis is independent of caspases and is typically associated with breakdown of the plasma membrane, organelle swelling and nuclear degradation that is accompanied by the release of nuclear factors like high mobility group box 1 (HMGB1) that trigger a potent inflammatory response (reviewed in Lotze and Tracey, 2005;Zeh and Lotze, 2005). NF-kB is commonly cytoprotective toward PCD caused by apoptosis or necrosis and its prosurvival activity has been observed in response to a variety of death-inducing stimuli like the proinflammatory cytokine TNFa, ultraviolet (UV) radiation, anticancer agents and B-cell receptor crosslinking (Wu et al, 1996;Grumont et al, 1998;Wang et al, 1998;van Antwerp et al, 1998;Owyang et al, 2001). However, NF-kB can promote cell death in response to certain stimuli and in certain cells (reviewed in Baldwin, 2001;Karin and Lin, 2002;Kucharczak et al, 2003).…”