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Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.

ABSTRACT: Proteasome inhibition has become synonymous with inhibition of NF-kappaB activity. However, hyperactive NF-kappaB responses often accompany physiological conditions marked by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-kappaB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-kappaB signaling induced by upstream mechanisms which are proteasome-independent. While this atypical pathway does not require proteasome for NF-kappaB nuclear translocation, a role for proteasome in regulating nuclear NF-kappaB remains unexplored. We now demonstrate that proteasome stringently controls transcription of inflammatory mediators regulated by this atypical NF-kappaB pathway. Proteolytic activity of the proteasome mediates the removal of the NF-kappaB subunit, p65/RelA, from inflammatory genes, thereby terminating atypical NF-kappaB-dependent transcriptional responses. For the first time, we demonstrate that both 19S and 20S components of the 26S proteasome complex are recruited to an inflammatory gene promoter; additionally, the 19S and 20S complexes appear to play distinct roles in the negative regulation of NF-kappaB-dependent transcription. By demonstrating that proteasome regulates the termination of atypical NF-kappaB-dependent transcriptional responses, these studies clearly indicate a novel, regulatory role for proteasome in atypical NF-kappaB signaling. Moreover, these results signal a potential interplay between lowered proteasomal function and increased inflammation and may explain why inflammation accompanies physiological conditions under which proteasomal function is compromised, such as during advancing age or following bortezomib treatment. Given this role for proteasome in inflammation resolution, restoration of proteasome function may constitute a novel mechanism for intervening in chronic inflammatory diseases.

SUBMITTER: Cullen SJ

PROVIDER: S-EPMC2812621 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.

Cullen Sarah J SJ Ponnappan Subramaniam S Ponnappan Usha U

Biochemical pharmacology 20091014 5

Proteasome inhibition has become synonymous with inhibition of NF-kappaB activity. However, hyperactive NF-kappaB responses often accompany physiological conditions marked by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-kappaB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-kappaB signaling induced by upstream mechanisms which are proteasome-independent. While this atypical pathway doe ...[more]

PMID: 19835847

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Project description:BackgroundSilicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFalpha) plays a central role in the pathogenesis of silicosis. TNFalpha signaling is mediated by the transcription factor, Nuclear Factor (NF)-kappaB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-kappaB activation represents a potential therapeutic strategy for silicosis.Methods/findingsIn the present work we evaluated the lung transplant database (May 1986-July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFalpha expressing macrophage and NF-kappaB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16-7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8-15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22-0.9 yr) following lung transplantation (2.4 yr; CI:1.5-3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IkappaB alpha mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica.ConclusionsAlthough limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-kappaB protects from silica-induced lung injury, epithelial cell specific NF-kappaB inhibition appears to aggravate the outcome of experimental silicosis.

Project description:A critical determinant in chronic gammaherpesvirus infections is the ability of these viruses to establish latency in a lymphocyte reservoir. The nuclear factor (NF)-kappaB family of transcription factors represent key players in B-cell biology and are targeted by gammaherpesviruses to promote host cell survival, proliferation, and transformation. However, the role of NF-kappaB signaling in the establishment of latency in vivo has not been addressed. Here we report the generation and in vivo characterization of a recombinant murine gammaherpesvirus 68 (gammaHV68) that expresses a constitutively active form of the NF-kappaB inhibitor, IkappaBalphaM. Inhibition of NF-kappaB signaling upon infection with gammaHV68-IkappaBalphaM did not affect lytic replication in cell culture or in the lung following intranasal inoculation. However, there was a substantial decrease in the frequency of latently infected lymphocytes in the lung (90% reduction) and spleens (97% reduction) 16 d post intranasal inoculation. Importantly, the defect in establishment of latency in lung B cells could not be overcome by increasing the dose of virus 100-fold. The observed decrease in establishment of viral latency correlated with a loss of activated, CD69(hi) B cells in both the lungs and spleen at day 16 postinfection, which was not apparent by 6 wk postinfection. Constitutive expression of Bcl-2 in B cells did not rescue the defect in the establishment of latency observed with gammaHV68-IkappaBalphaM, indicating that NF-kappaB-mediated functions apart from Bcl-2-mediated B-cell survival are critical for the efficient establishment of gammaherpesvirus latency in vivo. In contrast to the results obtained following intranasal inoculation, infection of mice with gammaHV68-IkappaBalphaM by the intraperitoneal route had only a modest impact on splenic latency, suggesting that route of inoculation may alter requirements for establishment of virus latency in B cells. Finally, analyses of the pathogenesis of gammaHV68-IkappaBalphaM provides evidence that NF-kappaB signaling plays an important role during multiple stages of gammaHV68 infection in vivo and, as such, represents a key host regulatory pathway that is likely manipulated by the virus to establish latency in B cells.

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Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.

Publications

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.

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