IL-1 Receptor-Associated Kinase and Low Molecular Weight GTPase RhoA Signal Molecules Are Required for Bacterial Lipopolysaccharide-Induced Cytokine Gene Transcription

Chen, Ling Yu; Zuraw, Bruce L.; Liu, Fu Tong; Huang, Shuang; Pan, Zhixing K.

doi:10.4049/jimmunol.169.7.3934

Cited by 56 publications

(45 citation statements)

References 39 publications

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“…Furthermore, studies have shown that inhibitors of Rho GTPases block the stimulation of macrophages with a mycoplasmal lipoprotein (25). A role for RhoA in TLR4-induced cytokine expression was postulated by two groups using different experimental approaches and cell types (26,27). We show in this study that RhoA controls a signaling cascade, which regulates NF-B trans activation without affecting I-B degradation.…”

Section: Discussionmentioning

confidence: 79%

The Low Molecular Weight GTPase RhoA and Atypical Protein Kinase Cζ Are Required for TLR2-Mediated Gene Transcription

Teusch

Lombardo

Eddleston

et al. 2004

The Journal of Immunology

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The Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell cycle progression, cell adhesion, and motility. In this study, we report that stimulation of TLR2 in human epithelial and monocytic cells leads to rapid and transient activation of RhoA. RhoA cooperated with the canonical I-κB kinase-mediated pathway that induces the release of NF-κB, in regulating the trans activation of the NF-κB subunit p65/RelA by affecting Ser311 phosphorylation, and subsequent cytokine production. Another consequence of TLR2 stimulation by bacterial derived products was the activation of atypical protein kinase C (PKC) ζ and association of this protein kinase with RhoA. Inhibition of PKCζ decreased NF-κB activation and p65/RelA trans activation without affecting I-κBα degradation. The observation of a transient, stimulus-dependent association of RhoA with PKCζ suggests that RhoA mediates at least partially its effect on gene transcription through atypical PKC. In contrast to previous studies, identifying Rac1-PI3K as an upstream element in TLR2-initiated response to NF-κB, PI3K signaling was not required for RhoA or PKCζ activity. These results indicate that multiple GTPase-regulated pathways emerge from stimulated Toll receptors, controlling different aspects of NF-κB-mediated gene transcription.

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Section: Discussionmentioning

confidence: 79%

The Low Molecular Weight GTPase RhoA and Atypical Protein Kinase Cζ Are Required for TLR2-Mediated Gene Transcription

Teusch

Lombardo

Eddleston

et al. 2004

The Journal of Immunology

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“…From a pathophysiological point of view it is important that C3 was shown to alter for example epithelial and endothelial barrier functions (Nusrat et al 1995;Stamatovic et al 2003), the signaling of immune cells including phagocytosis (Caron and Hall 1998), the production of cytokines (Chen et al 2002;Dreikhausen et al 2001), adhesion (Laudanna et al 1996), de-adhesion , and migration of immune cells (Worthylake et al 2001;Millan and Ridley 2005). A very recent study reported that C3stau-producing S. aureus form transcellular tunnels by inactivation of Rho, so-called macroapertures, which lead to the loss of barrier function in endothelial cells (Boyer et al 2006).…”

Section: The Pathogenetic Role Of C3-like Exoenzymesmentioning

confidence: 99%

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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The family of C3-like exoenzymes comprises seven bacterial ADP-ribosyltransferases of different origin. The common hallmark of these exoenzymes is the selective N-ADP-ribosylation of the low molecular mass GTPbinding proteins RhoA, B, and C and inhibition of signal pathways controlled by Rho GTPases. Therefore, C3-like exoenzymes were applied as pharmacological tools for analyses of cellular functions of Rho protein in numerous studies. Recent structural and functional analyses of C3-like exoenzymes provide detailed information on the molecular mechanisms and functional consequences of ADP-ribosylation catalyzed by these toxins. More recently additional non-enzymatic actions of C3-like ADP-ribosyltransferases have been identified showing that C3 transferases from Clostridium botulinum and Clostridium limosum form a GDI-like complex with the Ras-like low molecular mass GTPase Ral without ADP-ribosylation. These results add novel information on the molecular mode of action(s) of C3-like exoenzymes and are discussed in this review.

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“…Numerous stimuli can activate NF-B, including LPS, as well as other proinflammatory factors, such as TNF-␣ and IL-1 (8,9). Indeed, the LPSinduced activation of NF-B appears essential for proinflammatory cytokine synthesis in human peripheral blood monocytes (10).…”

mentioning

confidence: 99%

An Atypical Protein Kinase C (PKCζ) Plays a Critical Role in Lipopolysaccharide-Activated NF-κB in Human Peripheral Blood Monocytes and Macrophages

Huang¹,

Chen

Doerner³

et al. 2009

The Journal of Immunology

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We have reported that the bacterial LPS induces the activation of NF-κB and inflammatory cytokine gene expression and that this requires the activity of small GTPase, RhoA. In this study, we show that an atypical protein kinase C isozyme, PKCζ, associates functionally with RhoA and that PKCζ acts as a signaling component downstream of RhoA. Stimulation of monocytes and macrophages with LPS resulted in PKCζ activation and that inhibition of PKCζ activity blocks both LPS-stimulated activation of NF-κB and IL-1β gene expression. Our results also indicate that transforming growth factor β-activated kinase 1 acts as a signaling component downstream of PKCζ in cytokine gene transcription stimulated by LPS in human peripheral blood monocytes and macrophages. The specificity of this response suggests an important role for the Rho GTPase/PKCζ/transforming growth factor β-activated kinase 1/NF-κB pathway in host defense and in proinflammatory cytokine synthesis induced by bacterial LPS.

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IL-1 Receptor-Associated Kinase and Low Molecular Weight GTPase RhoA Signal Molecules Are Required for Bacterial Lipopolysaccharide-Induced Cytokine Gene Transcription

Cited by 56 publications

References 39 publications

The Low Molecular Weight GTPase RhoA and Atypical Protein Kinase Cζ Are Required for TLR2-Mediated Gene Transcription

The Low Molecular Weight GTPase RhoA and Atypical Protein Kinase Cζ Are Required for TLR2-Mediated Gene Transcription

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

An Atypical Protein Kinase C (PKCζ) Plays a Critical Role in Lipopolysaccharide-Activated NF-κB in Human Peripheral Blood Monocytes and Macrophages

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