Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1964091 | Cellular Signalling | 2007 | 12 Pages |
Abstract
Apoptosis is an important mechanism involved in regulating the number of macrophages present at sites of inflammation. Several lines of evidence indicate that blocking macrophage apoptosis can increase atherosclerosis. We previously reported that oxidized LDL can inhibit apoptosis in cultured bone marrow-derived macrophages. We used pertussis toxin (PTX) to test whether G protein coupled receptors are activated by oxLDL. PTX is a bacterial toxin that inhibits Gi activation by ADP-ribosylating the α subunit of Gi, preventing the subunit from interacting with receptors. Unexpectedly, we found that PTX by itself selectively blocks macrophage apoptosis in a dose-dependent manner. PTX acts in part by inhibiting acid sphingomyelinase activity which in turn prevents generation of ceramide, which is required for macrophage apoptosis. A Gi activator peptide, mastoparan, increased ceramide levels in macrophage and induced apoptosis, but pre-treatment with PTX partially overrode mastoparan-induced apoptosis. The anti-apoptotic effect of PTX was found to require ADP-ribosylation. PTX failed to prevent A-SMase activation or apoptosis in macrophages lacking TLR4. The anti-apoptotic effect of PTX involved the same signaling pathways as those of oxidized LDL, in that both inhibited acid sphingomyelinase, and activated the phosphoinositide 3 kinase (PI3K)/protein kinase B (PKB) pathway which leads to nuclear localization of the transcription factor NFκB and up-regulation of Bcl-XL. These results indicate that Gi proteins, TLR4, A-SMase and the PI3K/PKB pathway are crucial components for regulation of macrophage apoptosis.
Keywords
PTXC1PM-CSFBMDMPKBMTSPI3KERKMAPKMAPK/ERK kinaseAcetylsphingolipidssphingomyelinaseApoptosisceramideCeramide 1-phosphatepertussis toxinmacrophage colony stimulating factorPhosphatidylinositol 3-kinasephosphatidylinositol 3 kinaseMastoparanBone marrow-derived macrophagesMEKG-proteinmitogen-activated protein kinaseextracellular regulated kinase
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Authors
Shih Wei Wang, Kuljit Parhar, Kai Jen Chiu, Anthony Tran, Patricia Gangoiti, Jennifer Kong, Monika Gonzalez, Bill Salh, Vincent Duronio, Urs P. Steinbrecher, Antonio Gómez-Muñoz,