Serine and Cysteine Proteinase Inhibitors Prevent Nitric Oxide Production by Activated Macrophages by Interfering with Transcription of the Inducible NO Synthase Gene

Griscavage, Jeanette M.; Wilk, Sherwin; Ignarro, L J

doi:10.1006/bbrc.1995.2523

Cited by 62 publications

(38 citation statements)

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“…Cells containing the empty SFFV-neo vector served as a control. A representative experiment is shown inhibitor of calpain proteases 40 (K i 190 nM) and can also suppress the activity of the proteasome 34 (K i 670 nM), we do not rule out the possibility that its protective activity in this context might result from suppression of Bfl-1 cleavage, stabilization of full-length GFP-Bfl-1 or both.…”

Section: Resultsmentioning

confidence: 89%

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

et al. 2005

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Bfl-1/A1 is generally recognized as a Bcl-2-related inhibitor of apoptosis. We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover. Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells. Its anti-versus proapoptotic effect is regulated by two proteolytic events: (1) its constitutive proteasome-mediated turnover and (2) its TNF/cycloheximide (CHX)-induced cleavage by l-calpain, or a calpain-like activity, coincident with acquisition of a proapoptotic phenotype. In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains. This would be consistent with the generation of a proapoptotic Bax-like BH1-3 molecule. Overall, our studies uncovered two new regulatory mechanisms that play a decisive role in determining Bfl-1's prosurvival versus prodeath activities. These findings might provide important clues to counteract chemoresistance in tumor cells that highly express Bfl-1.

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Section: Resultsmentioning

confidence: 89%

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

et al. 2005

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“…As shown in Fig. 3, pretreatment of Jurkat cells with the NOS inhibitors L-NMMA and L-NAME, and TLCK which has been shown to inhibit NOS gene expression (51)(52)(53), attenuated SDF1␣-induced chemotaxis in a dose-dependent manner. L-NMMA pretreatment resulted in a 60 -70% inhibition at 0.1-1.0 mM (Fig.…”

Section: No Inhibitors Attenuate Sdf1␣-induced Chemotaxismentioning

confidence: 84%

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Cherla

Ganju

2001

The Journal of Immunology

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Stromal cell-derived factor 1α (SDF1α) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes. However, the molecular mechanisms regulating SDF1α-driven cell migration are not well defined. In this study, we have explored the roles of the second messenger NO and the transcription factor NF-κB in SDF1α-induced T cell migration. SDF1α treatment of Jurkat T cells increased the activity of NO synthase, which catalyzes the generation of NO. We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1α-induced migration, whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration-dependent manner. Furthermore, we observed that inhibitors of the transcription factor NF-κB, which is linked to NO signaling pathways, also significantly blocked the SDF1α-induced chemotactic response. However, these compounds did not have a significant effect on SDF1α-induced mitogen-activated protein kinase activity. In addition, the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate SDF1α-induced chemotaxis. AKT, which has been shown to mediate NO production, was also phosphorylated upon SDF1α stimulation. These studies suggest that NO-related signaling pathways may mediate SDF1α-induced chemotaxis, but not mitogen-activated protein kinase activation.

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“…Based on the fact that NO regulates expression and activity of NOS in mammalian cells (Griscavage et al, 1995 andGrumbach et al, 2005), we hypothesized that high induction of AsNOS by 2000 pg/ml TGF-β1 at 0 h resulted in early NO synthesis at levels that reduced AsNOS expression in the midgut at 36 h after feeding. We reported previously that the isoform non-specific NOS inhibitor L-NAME directly inhibited induced but not basal AsNOS activity in mosquito lysates (Luckhart et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

Luckhart

Lieber

Singh

et al. 2008

Experimental Parasitology

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Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-β1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-β1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-β1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-β1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-β1 is regulated by NO synthesis. These results suggest that TGF-β1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-β1 on inducible NO synthesis. .

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Serine and Cysteine Proteinase Inhibitors Prevent Nitric Oxide Production by Activated Macrophages by Interfering with Transcription of the Inducible NO Synthase Gene

Cited by 62 publications

References 0 publications

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

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