Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-κB signaling pathways and involves a novel feed-forward regulatory mechanism

Yin, Xi-Xi; Krikorian, Paul; Logan, Thomas J.; Csizmadia, Vilmos

doi:10.1007/s11010-009-0226-y

Cited by 34 publications

(16 citation statements)

References 26 publications

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“…Various strategies targeted at the NF-kB signaling pathway, such as NF-kB-specific decoy oligonucleotide (19), p65-specific antisense oligonucleotide (20), and IKKb-selective small molecule inhibitor (21), have demonstrated beneficial effects in experimental asthma models. Rip2 is not only a transcriptional product of NF-kB, but also a positive regulator of NF-kB activity (12). In this study, to our knowledge, we observed for the first time that lung Rip2 protein level was markedly elevated in experimental asthma, which was accompanied by increased NF-kB nuclear translocation and DNA binding.…”

Section: Discussionmentioning

confidence: 51%

“…Rip2 has been shown to mediate TCR signaling to NF-kB activation, cytokine production, and T cell proliferation, but the serine/threonine kinase activity is not required for NF-kB response (9)(10)(11). Rip2 is an inducible transcriptional product of NF-kB activation, and serves as a positive regulator of NF-kB pathway by binding to the IKK complex (12). In vitro study revealed that overexpression of Rip2 in HEK293T cells increases NF-kB activity and IL-1b production (13).…”

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confidence: 99%

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Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Goh

Cook

Upton

et al. 2013

The Journal of Immunology

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Persistent activation of NF-κB has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-κB activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-κB activity. We investigated potential protective effects of Rip2 gene silencing using small interfering RNA (siRNA) in an OVA-induced mouse asthma model. Rip2 protein level was found to be upregulated in allergic airway inflammation. A potent and selective Rip2 siRNA given intratracheally knocked down Rip2 expression in OVA-challenged lungs and reduced OVA-induced increases in total and eosinophil counts, and IL-4, IL-5, IL-13, IL-1β, IL-33, and eotaxin levels in bronchoalveolar lavage fluid. Rip2 silencing blocked OVA-induced inflammatory cell infiltration and mucus hypersecretion as observed in lung sections, and mRNA expression of ICAM-1, VCAM-1, E-selectin, RANTES, IL-17, IL-33, thymic stromal lymphopoietin, inducible NO synthase, and MUC5ac in lung tissues. In addition, elevation of serum OVA-specific IgE level in mouse asthma model was markedly suppressed by Rip2 siRNA, together with reduced IL-4, IL-5, and IL-13 production in lymph node cultures. Furthermore, Rip2 siRNA-treated mice produced significantly less airway hyperresponsiveness induced by methacholine. Mechanistically, Rip2 siRNA was found to enhance cytosolic level of IκBα and block p65 nuclear translocation and DNA-binding activity in lung tissues from OVA-challenged mice. Taken together, our findings clearly show that knockdown of Rip2 by gene silencing ameliorates experimental allergic airway inflammation, probably via interruption of NF-κB activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma.

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Section: Discussionmentioning

confidence: 51%

mentioning

confidence: 99%

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Goh

Cook

Upton

et al. 2013

The Journal of Immunology

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“…It contains a serine/threonine kinase domain and a caspase activation and recruitment domain (35). It can be recruited to TNFR1 via TRAF proteins and can activate caspases and NFB signaling (36,37). Although RIP2 phosphorylation at 10 min did not correlate well with apoptosis, it did correlate with both p38 phosphorylation (r ϭ 0.90, p Ͻ 0.0001) and JNK phosphorylation (r ϭ 0.87, p Ͻ 0.0001), and RIP2 has previously been shown to lie upstream of these proteins mechanistically (38 -40).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between Receptor Tyrosine Kinase and Tumor Necrosis Factor-α Signaling Networks Regulates Apoptosis but not Proliferation

Beyer

MacBeath

2012

Molecular & Cellular Proteomics

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Although many of the signaling networks activated by receptor tyrosine kinases (RTKs) and cytokine receptors are well understood, how these networks interconnect is much less clear. We set out to determine how cells respond to simultaneous exposure to opposing signals and how their downstream networks process this information. Using six isogenic cell lines, each stably transfected with a different RTK, we found that, in each case, the cognate growth factor induced proliferation, whereas TNF␣ induced apoptosis. Surprisingly, when the cells were treated simultaneously with growth factor and TNF␣, the growth factor enhanced, rather than antagonized, TNF␣-induced cell death. In contrast, TNF␣ had no effect on growth factor-induced proliferation, suggesting that cross-talk between these networks is unidirectional. A quantitative, system-wide study of signaling at early and late time points corroborated this observation: proteins in the RTK networks were not affected by TNF␣ treatment, but proteins in the TNF␣ network were affected by growth factors. These studies also highlighted the stress mitogen-activated protein kinase proteins p38 and c-Jun Nterminal kinase as the key nodes of signal integration, and their activation states at an early time point correlated well with subsequent measurements of apoptosis. Knocking down cRaf reduced the growth factor enhancement of TNF␣-induced apoptosis, highlighting its role as a regulator of network cross-talk upstream of p38 and c-Jun N-terminal kinase. Overall, we found that when cells encounter conflicting stimuli, their phenotypic response is determined not by the sum of isolated processes, but by how their signaling networks interconnect. This underscores the need to build mechanistic models of network integration as a first step in predicting cellular behavior in complex settings and in rationally designing combination therapies.

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“…Immunopharmacological intervention against atherosclerosis attracts major interest. Rip2 recently has been suggested to be a key target for immune intervention to atherosclerosis, 19 as well as several other pathological disorders. 36,37 However, the results of the present study clearly demonstrate that immunosuppression targeting Rip2 may have unexpected negative consequences, eg, subendothelial lipid accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…14 -18 Furthermore, it was demonstrated recently that the regulation of Rip2 involves a novel feedforward regulatory mechanism: Rip2 not only positively regulates NF-B activity, but inflammatory cytokines that activate the NF-B pathway induce increased Rip2 expression. 19 These studies thus suggest the therapeutic potential of inhibiting Rip2 to inhibit inflammation and thus protect against the development of atherosclerosis. …”

mentioning

confidence: 96%

Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation

Levin

Jirholt²,

Wramstedt³

et al. 2011

Circulation Research

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Rationale:The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-B (NFB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.Objective: We hypothesized that inhibition of Rip2 would protect against development of atherosclerosis. Methods and Results: Surprisingly, and contrary to our hypothesis, we found that mice transplanted with Rip2؊/؊ bone marrow displayed markedly increased atherosclerotic lesions despite impaired local and systemic inflammation. Moreover, lipid uptake was increased whereas immune signaling was reduced in Rip2 macrophages. Further analysis in Rip2؊/؊ macrophages showed that the lipid accumulation was scavengerreceptor independent and mediated by Toll-like receptor 4 (TLR4)-dependent lipid uptake. Ⅲ macrophages L ow-density lipoproteins (LDL) are the major extracellular carriers of cholesterol and, as such, play important physiological roles in cellular function and regulation of metabolic pathways. However, under pathological conditions of hyperlipidemia, cholesterol is diverted from its physiological targets and accumulates in lipid-loaded macrophages ("foam cells") in the vascular wall. [1][2][3][4] This pathological deposition of atherogenic lipoproteins activates the inflammatory response that characterizes atherosclerosis. Furthermore, by stimulating the synthesis and secretion of proteoglycans, 5,6 this inflammation further accelerates retention of atherogenic lipoproteins. Thus, lipid accumulation and inflammation are closely linked in atherogenesis. [7][8][9][10][11] The molecular mechanisms that link retention of atherogenic lipoproteins and activation of the inflammatory response are still unclear. Recent evidence implies a key role for the innate immune system and pathogen patternrecognition receptors, in particular the membrane-bound Toll-like receptors (TLRs). 12 Ligand binding to these receptors results in activation of the proinflammatory transcription factor nuclear factor-B (NF-B) and expression of proinflammatory molecules. 12,13 The receptor-interacting protein 2 (Rip2) is a serine/ threonine kinase that activates NF-B and is reported to mediate signaling through both TLRs and Nod-like receptors, although its involvement in TLR signaling has been questioned recently. 14 -18 Furthermore, it was demonstrated recently that the regulation of Rip2 involves a novel feedforward regulatory mechanism: Rip2 not only positively regulates NF-B activity, but inflammatory cytokines that activate the NF-B pathway induce increased Rip2 expression. 19 These studies thus suggest the therapeutic potential of inhibiting Rip2 to inhibit inflammation and...

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Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-κB signaling pathways and involves a novel feed-forward regulatory mechanism

Cited by 34 publications

References 26 publications

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Cross-talk between Receptor Tyrosine Kinase and Tumor Necrosis Factor-α Signaling Networks Regulates Apoptosis but not Proliferation

Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation

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