MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation

Górska, M.; Qiang, Liang; Stafford, Susan; Goplen, N.; Dharajiya, Nilesh; Guo, Lei; Sur, Sanjiv; Gaestel, Matthias; Alam, Rafeul

doi:10.1084/jem.20062621

Cited by 88 publications

(89 citation statements)

References 57 publications

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“…The major phosphoproteins and nuclear transcription factors evidenced in this investigation are reported. Arrows with dashed lines indicate the putative interactions between the different phosphoproteins and transcription factors as obtained from the literature and described in the text (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Dashed arrows are related to the putative transmembrane signaling of P. aeruginosa (black lines), IL-1b (red lines), or TNF-a (blue lines).…”

Section: Discussionmentioning

confidence: 99%

“…Another member of the RSK family, the mitogen-and stress-activated kinase-2 (MSK2), has been reported to be a substrate of p38a, which is able to activate both CREB and AP-1 (19). The p38 effectors include also the small heat shock protein 27 (HSP27), which is involved in inflammatory processes, together with MK2 kinase, with both activating NF-kB (20). Additionally, HSP27 has been reported to be recruited in IL-1b-and TNF-a-dependent IL-8 gene transcription in HeLa cells (21).…”

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confidence: 99%

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Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells

Bezzerri

Borgatti

Finotti

et al. 2011

The Journal of Immunology

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IL-8 released from bronchial epithelial cells infected with Pseudomonas aeruginosa plays a crucial role in the chronic lung pathology of patients affected by cystic fibrosis. Novel anti-inflammatory approaches will benefit from a thorough understanding of the regulatory mechanisms involved in the transcription of this chemokine to identify potential pharmacological targets. We addressed this issue by investigating the role of phosphoproteins and transcription factors (TFs) on transcription of IL-8 gene in the human bronchial epithelial IB3-1, CuFi-1, and Calu-3 cells. P. aeruginosa increased the basal phosphorylation of the ERK1/2 pathway components 90-kDa ribosomal S6 kinase (RSK)1/2 and mitogen- and stress-activated kinase-2 and of the p38 MAPK pathway components p38α/δ/γ and heat shock protein 27 (HSP27). The involvement of these kinases in the expression of IL-8 gene was confirmed with pharmacological inhibitors of ERK1/2, RSK, p38, and HSP27 both at transcription and secretion levels. Transfection of TF decoy oligodeoxynucleotides, designed to interfere with the interaction of the TFs NF-κB, NF-IL6, AP-1, CREB, and CHOP with the corresponding consensus sequences identified in the IL-8 promoter, reduced the P. aeruginosa-dependent transcription of IL-8, suggesting their participation in the transcriptional machinery. Stimulation of IB3-1 cells with IL-1β led to a similar pattern of activation, whereas the pattern of phosphoproteins and of TFs modulated by TNF-α differentiated sharply. In conclusion, the results highlight a novel role for RSK1/2 and HSP27 phosphoproteins and of the cooperative role of the TFs NF-κB, NF-IL6, AP-1, CHOP, and CREB in P. aeruginosa-dependent induction of transcription of the IL-8 gene in human bronchial epithelial cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells

Bezzerri

Borgatti

Finotti

et al. 2011

The Journal of Immunology

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“…Recipient mice were challenged intranasally with OVA (150 mg in 15 ml PBS) 24 h before and 24, 48, and 72 h after injection. Forty-eight hours after the last challenge, the airway reactivity to aerosolized methacholine was measured by the respiratory apparatus Flexivent (Scireq, Montreal, Quebec, Canada) (22), and bronchoalveolar lavage (BAL) was performed. Lungs were sectioned and stained with H&E, periodic acid and fluorescent Schiff's reagent or anti-GFP Ab and DAPI as explained elsewhere (22,25).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Lungs were sectioned and stained with H&E, periodic acid and fluorescent Schiff's reagent or anti-GFP Ab and DAPI as explained elsewhere (22,25). The morphometric analysis of stained sections was performed as described (22).…”

Section: Flow Cytometrymentioning

confidence: 99%

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Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Górska

Goplen²,

Qiang³

et al. 2010

The Journal of Immunology

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The Th2 bias is a hallmark of allergic diseases. In this study, we show that the Th1 versus Th2 balance and the development of allergic asthma are strongly affected by the signaling protein uncoordinated 119 (Unc119). The expression of this adaptor protein is significantly increased in Th2 cells. Unc119 activates the Src family and inhibits the Abl family of tyrosine kinases. The activated Src family kinase Lck stimulates the activity of Itk and the expression of the transcription factor JunB. As a result, Unc119 promotes IL-4 production. Through inhibition of Abl kinases, Unc119 dampens IFN-γ production. Using adoptive transfer of Unc119-knockdown CD4 T cells, we show a critical role for Unc119 in the development of eosinophilic inflammation of airways, mucus production, and bronchial hyperreactivity in a mouse model. Intriguingly, the expression of the Unc119 protein is enhanced in CD4 T cells from patients with asthma. We speculate that the heightened expression of Unc119 promotes Th2, inhibits Th1 differentiation, and contributes to the pathogenesis of asthma in humans.

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Mitogen-activated protein kinase 2 regulates physiological and pathological bone turnover

Braun¹,

Lepper²,

Heiland³

et al. 2012

Journal of Bone and Mineral Research

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The objective of this study was to investigate the role of the serine-threonine kinase mitogen-activated protein kinase 2 (MK2) in bone homeostasis. Primary bone cell cultures from MK2 þ/þ and MK2 -/-mice were assessed for osteoclast and osteoblast differentiation, bone resorption, and gene expression. Bone architecture of MK2 þ/þ and MK2 -/-mice was investigated by micro-computed tomography and histomorphometry. Ovariectomy was performed in MK2 þ/þ and MK2 -/-mice to assess the role of MK2 in postmenopausal bone loss. Osteoclastogenesis, bone resorption, and osteoclast gene expression were significantly impaired in monocytes from MK2 -/-compared to MK2 þ/þ mice. Mechanistically, loss of MK2 causes impaired DNA binding of c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) to tartrate-resistant acid phosphatase (TRAP) and the calcitonin receptor gene promoter. In addition, MK2 -/-mice showed an age-dependent increase in trabecular bone mass and cortical thickness, fewer osteoclasts, and lower markers of bone resorption than MK2 þ/þ mice. Furthermore, MK2 -/-mice were protected from ovariectomy-induced bone loss. Osteoblastogenesis and bone formation were unchanged in MK2 -/-mice, whereas osteoblast expression of osteoprotegerin (OPG) and serum levels of OPG were higher in MK2 -/-than in MK2 þ/þ mice. Loss of MK2 effectively blocks bone resorption and prevents the development of postmenopausal bone loss. Smallmolecule inhibitors of MK2 could thus emerge as highly effective tools to block bone resorption and to treat postmenopausal bone loss. ß

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MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation

Cited by 88 publications

References 57 publications

Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells

Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells

Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Mitogen-activated protein kinase 2 regulates physiological and pathological bone turnover

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