Proteasomal inhibition upregulates the endogenous MAPK deactivator MKP-1 in human airway smooth muscle: Mechanism of action and effect on cytokine secretion

Moutzouris, John P.; Che, Wenchi; Ramsay, Emma E.; Manetsch, Melanie; Alkhouri, Hatem; Bjorkman, Anna M.; Schuster, Friederike S; Ge, Qi; Ammit, Alaina J.

doi:10.1016/j.bbamcr.2009.12.007

Cited by 32 publications

(31 citation statements)

References 31 publications

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“…MG262 reduced the IL-1␤-and TNF␣-induced release of IL-6 and IL-8 by both nasal mucosa and polyp fibroblasts. In agreement with our results, a decrease in IL-6 production has been reported after proteasome inhibition of TNF-␣-stimulated airway smooth muscle cells (Moutzouris et al, 2010), lipopolysaccharide plus phorbol 12-myristate 13-acetate-stimulated U937 monocytes (OrtizLazareno et al, 2008), and multiple myeloma cell lines (Hideshima et al, 2001). Controversial results have been obtained with regard to IL-8: in line with our results, proteasome inhibition of lipopolysaccharide-stimulated macrophages has led to decreased IL-8 levels (Cuschieri et al, 2004), but increased IL-8 levels have also been reported after the proteasome inhibition of various cell types (Hipp et al, 2002;Gerber et al, 2004).…”

Section: Discussionsupporting

confidence: 92%

Proteasome Inhibition Reduces Proliferation, Collagen Expression, and Inflammatory Cytokine Production in Nasal Mucosa and Polyp Fibroblasts

Pujols

Fernández-Bertolín²,

Fuentes³

et al. 2012

J Pharmacol Exp Ther

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Proteasome inhibitors, used in cancer treatment for their proapoptotic effects, have anti-inflammatory and antifibrotic effects on animal models of various inflammatory and fibrotic diseases. Their effects in cells from patients affected by either inflammatory or fibrotic diseases have been poorly investigated. Nasal polyposis is a chronic inflammatory disease of the sinus mucosa characterized by tissue inflammation and remodeling. We tested the hypothesis that proteasome inhibition of nasal polyp fibroblasts might reduce their proliferation and inflammatory and fibrotic response. Accordingly, we investigated the effect of the proteasome inhibitor Z-Leu-Leu-Leu-B(OH) 2 (MG262) on cell viability and proliferation and on the production of collagen and inflammatory cytokines in nasal polyp and nasal mucosa fibroblasts obtained from surgery specimens. MG262 reduced the viability of nasal mucosa and polyp fibroblasts concentration-and time-dependently, with marked effects after 48 h of treatment. The proteasome inhibitor bortezomib provoked a similar effect. MG262-induced cell death involved loss of mitochondrial membrane potential, caspase-3 and poly(ADP-ribose) polymerase activation, induction of c-Jun phosphorylation, and mitogen-activated protein kinase phosphatase-1 expression. Low concentrations of MG262 provoked growth arrest, inhibited DNA replication and retinoblastoma phosphorylation, and increased expression of the cell cycle inhibitors p21 and p27. MG262 concentrationdependently inhibited basal and transforming growth factor-␤-induced collagen mRNA expression and interleukin (IL)-1␤-induced production of IL-6, IL-8, monocyte chemoattractant protein-1, regulated on activation normal T cell expressed and secreted, and granulocyte/macrophage colony-stimulating factor in both fibroblast types. MG262 inhibited IL-1␤/tumor necrosis factor-␣-induced activation of nuclear factor-B. We conclude that noncytotoxic treatment with MG262 reduces the proliferative, fibrotic, and inflammatory response of nasal fibroblasts, whereas high MG262 concentrations induce apoptosis.

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Section: Discussionsupporting

confidence: 92%

Proteasome Inhibition Reduces Proliferation, Collagen Expression, and Inflammatory Cytokine Production in Nasal Mucosa and Polyp Fibroblasts

Pujols

Fernández-Bertolín²,

Fuentes³

et al. 2012

J Pharmacol Exp Ther

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“…Studies have supported a role for MKP-1 as a negative feedback regulator of the p38 MAPK pathway and as a repressor of proremodeling functions of ASM cells (8,12,19,23,27). MKP-1 has been widely explored; however, its potential interaction with TTP is less well studied.…”

Section: Discussionmentioning

confidence: 99%

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

Prabhala

Bunge

Rahman

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Prabhala P, Bunge K, Rahman MM, Ge Q, Clark AR, Ammit AJ. Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1. Am J Physiol Lung Cell Mol Physiol 308: L973-L980, 2015. First published February 27, 2015 doi:10.1152/ajplung.00219.2014.-Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPKmediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-␣. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-␣-TNFR1. Rather, the biphasic nature of TNF-␣-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling. p38 MAPK; tristetraprolin; MKP-1; inflammation; IL-6 MANY CHRONIC INFLAMMATORY diseases are a common consequence of overactive inflammatory signaling pathways. Hence, using these pathways as potential drug targets represents a way to re-establish control and attenuate the severity of such chronic inflammatory diseases. Asthma is a chronic inflammatory disease, which is characterized by reversible airway obstruction, structural remodeling, and airway hyperresponsiveness. A plethora of proinflammatory cytokines have been implicated in the pathophysiology of asthma. The common therapies for asthma include glucocorticoids and ␤ 2 -agonists; however, there is still a proportion of the population for which this treatment is ineffective. Hence, a need has arisen to find alternative anti-inflammatory strategies, such as using smallmolecule inhibitors of inflammatory cascades or using agents that could increase activity of anti-inflammatory proteins. To achieve this goal, a greater understanding of the regulatory networks that control cytokines are u...

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“…This p38 MAPK upregulation occurs very soon after the cell is stimulated by some extracellular trigger. Our own studies in human airway smooth muscle cells indicate that activation of p38 MAPK occurs as early as 10-15 minutes after stimulation (Quante et al, 2008;Moutzouris et al, 2010) and possibly even earlier. TTP is a known substrate for p38 MAPK and MK2, both of which are required for the full induction of TTP expression.…”

Section: Regulation Of the Temporal Kinetics Of Ttp By P38 Mapkmentioning

confidence: 75%

“…During this period when TTP is inactive, the cytokine mRNA is stabilized and results in a wave of cytokine upregulation, peaking at 1 hour (Balakathiresan et al, 2009). This is derived from the fact that active p38 MAPK has a peak at 15-30 minutes, with activation returning to basal levels after about 1 hour (Quante et al, 2008;Moutzouris et al, 2010). Once p38 MAPK activation has subsided, MK2 is no longer phosphorylated and hence is unable to phosphorylate TTP.…”

Section: Regulation Of the Temporal Kinetics Of Ttp By P38 Mapkmentioning

confidence: 99%

Tristetraprolin and Its Role in Regulation of Airway Inflammation

Prabhala

Ammit

2014

Mol Pharmacol

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Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are clinically and socioeconomically important diseases globally. Currently the mainstay of anti-inflammatory therapy in respiratory diseases is corticosteroids. Although corticosteroids have proven clinical efficacy in asthma, many asthmatic inflammatory conditions (e.g., infection, exacerbation, and severe asthma) are not responsive to corticosteroids. Moreover, despite an understanding that COPD progression is driven by inflammation, we currently do not have effective anti-inflammatory strategies to combat this disease. Hence, alternative anti-inflammatory strategies are required. p38 mitogen-activated protein kinase (MAPK) has emerged as an important signaling molecule driving airway inflammation, and pharmacological inhibitors against p38 MAPK may provide potential therapies for chronic respiratory disease. In this review, we discuss some of the recent in vitro and in vivo studies targeting p38 MAPK, but suggest that p38 MAPK inhibitors may prove less effective than originally considered because they may block antiinflammatory molecules along with proinflammatory responses. We propose that an alternative strategy may be to target an antiinflammatory molecule farther downstream of p38 MAPK, i.e., tristetraprolin (TTP). TTP is an mRNA-destabilizing, RNAbinding protein that enhances the decay of mRNAs, including those encoding proteins implicated in chronic respiratory diseases. We suggest that understanding the molecular mechanism of TTP expression and its temporal regulation will guide future development of novel anti-inflammatory pharmacotherapeutic approaches to combat respiratory disease.

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Proteasomal inhibition upregulates the endogenous MAPK deactivator MKP-1 in human airway smooth muscle: Mechanism of action and effect on cytokine secretion

Cited by 32 publications

References 31 publications

Proteasome Inhibition Reduces Proliferation, Collagen Expression, and Inflammatory Cytokine Production in Nasal Mucosa and Polyp Fibroblasts

Proteasome Inhibition Reduces Proliferation, Collagen Expression, and Inflammatory Cytokine Production in Nasal Mucosa and Polyp Fibroblasts

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

Tristetraprolin and Its Role in Regulation of Airway Inflammation

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