TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Liu, Hongtao; Ma, Yingyu; Pagliari, Lisa J.; Perlman, Harris; Yu, Chenfei; Lin, Anning; Pope, Richard M.

doi:10.4049/jimmunol.172.3.1907

Cited by 80 publications

(72 citation statements)

References 76 publications

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“…We attempted to induce apoptosis using various activators of the extrinsic pathway of apoptosis (e.g., TNF-a, FasL, TRAIL), but we found that these agents did not induce apoptosis in BMDMs, even when cultured in the absence or presence of serum and LCM (not shown). These results are consistent with earlier studies that report significant resistance to apoptosis in mature macrophages subjected to growth factor withdrawal or addition of activators of the extrinsic pathway of cell death (21)(22)(23). Because macrophages are known to be susceptible to apoptosis induced by ER stress (24-27), we determined whether expression of BCAP influenced survival after addition of thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that activates ER stress and the intrinsic pathway of apoptosis (28).…”

Section: Bcap Is Required For Maximal Protection Against Apoptosis Insupporting

confidence: 80%

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Song

Chew

Dale

et al. 2011

The Journal of Immunology

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Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP−/− mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-κB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress.

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Section: Bcap Is Required For Maximal Protection Against Apoptosis Insupporting

confidence: 80%

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Song

Chew

Dale

et al. 2011

The Journal of Immunology

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“…Similarly, in different cell types, there is an inverse relationship between TNF-α-induced activation of the JNK module and NFκB. In cases where there is JNK module activation, NFκB stimulation is suppressed whereas in other cases increased NFκB stimulation is associated with less JNK activation [40][41][42][43]. In the present study, we found that Erk, JNK, and p38 MAP kinase pathways were not activated by application of TNF-α.…”

Section: Discussionsupporting

confidence: 49%

TNF-α promotes cell survival through stimulation of K+ channel and NFκB activity in corneal epithelial cells

Wang

Reinach

2005

Experimental Cell Research

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Tumor necrosis factor (TNF-α) in various cell types induces either cell death or mitogenesis through different signaling pathways. In the present study, we determined in human corneal epithelial cells how TNF-α also promotes cell survival. Human corneal epithelial (HCE) cells were cultured in DMEM/F-12 medium containing 10% FBS. TNF-α stimulation induced activation of a voltage-gated K + channel detected by measuring single channel activity using patch clamp techniques. The effect of TNF-α on downstream events included NFκB nuclear translocation and increases in DNA binding activities, but did not elicit ERK, JNK, or p38 limb signaling activation. TNF-α induced increases in p21 expression resulting in partial cell cycle attenuation in the G 1 phase. Cell cycle progression was also mapped by flow cytometer analysis. Blockade of TNF-α-induced K + channel activity effectively prevented NFκB nuclear translocation and binding to DNA, diminishing the cell-survival protective effect of TNF-α. In conclusion, TNF-α promotes survival of HCE cells through sequential stimulation of K + channel and NFκB activities. This response to TNF-α is dependent on stimulating K + channel activity because following suppression of K + channel activity TNF-α failed to activate NFκB nuclear translocation and binding to nuclear DNA.

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“…NF-κB activation usually precedes the apoptotic effects of IFN-α, that is why IFN-α activates NF-κB in all cell types, while it very rarely induces apoptosis (for reviews see (Gaur and Aggarwal, 2003). However, if NF-κB pathway is inhibited beforehand, macrophages become sensitive to IFN-α-induced apoptosis (Liu et al, 2004). Our experiment showed that the NF-κB pathway had already been down-regulated when IFN-α concentration was elevated on AM cultures, further explaining why apoptosis of macrophages was further facilitated in the event of a high IFN-α concentration.…”

Section: Discussionmentioning

confidence: 99%

Amniotic membrane induces apoptosis of interferon-γ activated macrophages in vitro

Kawakita

et al. 2006

Experimental Eye Research

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Amniotic membrane (AM) used as a temporary or permanent graft for ocular surface reconstruction has a potent anti-inflammatory effect. We would like to investigate the mechanism whereby AM induces macrophage apoptosis in vitro. Mouse macrophages, Raw 264.7 cells, were cultured on plastic, type I collagen, corneal stromal slice or AM stromal matrix in serum-free medium with or without interferon-γ (IFN-γ). Cells were stained by LIVE/DEAD assay, Hoechst-33342, and TUNEL assay for cell death and apoptosis. Cell lysates and conditioned media were analysed by Cell Death Detection ELISA assay for quantitation of apoptosis. Conditioned media were also analysed by Griess assay for the nitrite concentration and ELISA assay for tumour necrosis factor alpha (IFN-α) concentration. Lysates of cells were subjected to Western blot analyses of IKK-α, IKK-β, p65 (RelA) subunit of nuclear factor κB (NF-κB), total Akt, phospho-Akt (Ser473), and phospho-FKHR (Thr24)/phosphor-FKHRL1 (Thr32). At 48 hr after cultivation, cells showed a low level of apoptosis when cultured on plastic, type I collagen and corneal stromal slice with or without IFN-γ and on AM without IFN-γ. Nevertheless, cells showed a significant increase of apoptosis when cultured on AM with IFN-γ activation, and this phenomenon became apparent only after 48 hr. IFN-γ-activated macrophages on plastic continuously produced nitric oxide (NO) and IFN-α during 72 hr culturing. In contrast, there was no NO and IFN-α production after 48 hr culture on AM. NO inhibitors, L-NMMA and L-NIL, attenuated NO production of IFN-γ-activated macrophages on AM, while apoptosis was not decreased accordingly. Expression of IKK-α, IKK-β, p65 (RelA) subunit of NF-κB total Akt, phosopho-Akt (Ser473), and phospho-FKHR (Thr24)/FKHRL1 (Thr32) was all down-regulated in IFN-γ-activated macrophages cultured on AM. In conclusion, AM stromal matrix induces apoptosis of IFN-γ activated, but not non-activated macrophages, not through the generation of NO, but instead by down-regulating anti-apoptotic NF-κB and Akt-FKHR signalling pathways.

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TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Cited by 80 publications

References 76 publications

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

TNF-α promotes cell survival through stimulation of K+ channel and NFκB activity in corneal epithelial cells

Amniotic membrane induces apoptosis of interferon-γ activated macrophages in vitro

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