Protein kinase Cδ and protein tyrosine kinase regulate peptidoglycan-induced nuclear factor-κB activation and inducible nitric oxide synthase expression in mouse peritoneal macrophages in vitro

Bhatt, Kunal H.; Pandey, R. K.; Dahiya, Yogesh; Sodhi, Ajit

doi:10.1016/j.molimm.2009.10.029

Cited by 30 publications

(27 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). Our findings are consistent with previous studies in other models demonstrating that PKCδ is a critical regulator of iNOS expression in mouse peritoneal macrophages (Bhatt et al, 2010), human leukemia cells (Deb et al, 2003), and BV-2 cells (Wen et al, 2011). Likewise, in the SN of MPTP-treated PKCδ KO mice, a concomitant reduction of iNOS mRNA and gp91phox expression levels was detected in the nigral tissue at 24 h after MPTP treatment.…”

Section: Discussionsupporting

confidence: 93%

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon

Singh

Lawana

et al. 2016

Neurobiology of Disease

View full text Add to dashboard Cite

Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCδ activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCδ contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including α-synuclein, tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCδ with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKCδ in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCδ in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCδ in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKCδ activated NFκB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFκB led to translocation of the p65 subunit to the nucleus, IκBα degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We...

show abstract

Section: Discussionsupporting

confidence: 93%

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon

Singh

Lawana

et al. 2016

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…In particular, we can suppose that PKC might act as an upstream regulator of NF-κB, STAT1 and CREB. The hypothesis of the activation of the PKC/NF-κB pathway following NO donors' administration, that contributes to the induction of allodynia/hyperalgesia, was confirmed by studies conducted on murine microglia showing that LPS-and peptidoglycan-induced iNOS production appears to be mediated by a signaling pathway involving the sequential of PKC and NF-κB activation (Bhatt et al 2010;Wen et al 2011). Similarly, we can suppose that PKC might be involved in the NO-induced supraspinal activation of STAT1.…”

Section: Discussionmentioning

confidence: 65%

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Galeotti¹,

Ghelardini²

2012

Psychopharmacology

View full text Add to dashboard Cite

Rationale Hypericum perforatum, popularly called St. John's wort (SJW), is a medicinal plant mainly used as antidepressant with a favorable safety profile than standard antidepressants. Some studies have also documented other SJW bioactivities, including pain modulation. Objectives The aim of this study was to demonstrate the capability of SJW to relieve nitric oxide (NO)-induced nociceptive hypersensitivity and identify the effective component. Methods Nociceptive hypersensitivity induced by administration of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) was assessed by cold and hot plate tests. The cellular pathways and molecular targets involved were investigated by Western blotting. Results GTN and SNP produced a prolonged allodynia and hyperalgesia in mice. A single oral administration of low doses of an SJW dried extract or purified hypericin reversed the NO donor-induced nociceptive behavior whereas hyperforin and flavoinoids were ineffective. Investigating into the cellular pathways involved, an increased CREB and STAT1 phosphorylation, and activation of NF-κB were detected within PAG and thalamus following NO donors' administration. These cellular events were prevented by SJW or hypericin. Since hypericin showed PKC blocking properties, a role of PKC as an upstream modulator of these transcription factors was hypothesized. NO donors increased expression and phosphorylation of protein kinase C (PKC) γ and ε isoforms, molecular events prevented by SJW or hypericin. Conclusions SJW reversed NO-induced nociceptive hypersensitivity through the blockade of a supraspinal signaling pathway involving a PKC-dependent CREB, STAT1 and NF-κB activation due to presence of hypericin. These data indicate SJW/hypericin as a therapeutic perspective for pain treatment.

show abstract

“…We have previously reported the role of protein tyrosine kinase, PKC␦ and NF-B in PGN (S. aureus)-induced iNOS expression and NO production in macrophages (5). In the present study, the role of MAPKs and transactivating molecules (NF-B and AP-1) in PGN-induced iNOS expression and NO production have been investigated.…”

Section: Discussionmentioning

confidence: 85%

“…Peptidoglycan (PGN), the main cell wall component of Gram-positive bacteria, activates host cells through the pattern recognition receptors Toll-like receptor 2 (TLR2) and CD14 and induces the expression of more than 120 genes in human monocytes (23,43,51). PGN has been reported to stimulate a variety of signal transduction elements such as MyD88, TRAF, protein tyrosine kinases, protein kinase C␦, and mitogen-activated protein kinases (MAPKs) in macrophages and induces the production of inflammatory cytokines and nitric oxide (5,8,19,48,50,51). However, the roles of MAPKs in PGN-induced activation of macrophages are still not well defined.…”

mentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinases in Peptidoglycan-Induced Expression of Inducible Nitric Oxide Synthase and Nitric Oxide in Mouse Peritoneal Macrophages: Extracellular Signal-Related Kinase, a Negative Regulator

Bhatt

Sodhi

Chakraborty

2011

Clin Vaccine Immunol

Self Cite

View full text Add to dashboard Cite

The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are important host defense mechanisms against pathogens in mononuclear phagocytes. The objectives of this study were to examine the roles of mitogen-activated protein kinases ( mapk in macrophages, albeit with differential activation kinetics. Using a selective inhibitor of JNK (SP600125) and JNK1/2 small interfering RNA (siRNA) knocked-down macrophages, it was observed that PGN-induced iNOS and NO expression is significantly inhibited. This suggested that JNK MAPK plays an essential role in PGN-induced iNOS expression and NO production. In contrast, inhibition of the ERK pathway using PD98059 dose dependently enhanced PGN-induced iNOS expression and NO production. PGN-induced ERK activation was attenuated in ERK1/2 siRNA knocked-down macrophages; however, NO and iNOS expression were significantly enhanced. An electrophoretic mobility shift assay showed that SP600125 inhibited PGN-induced NF-B and AP-1 activation, whereas inhibition of the ERK pathway enhanced NF-B activation, but with no effect on AP-1. These results indicate that the JNK MAPK positively regulate PGN-induced iNOS and NO expression by activating NF-B and AP-1 transcription factors, whereas the ERK pathway plays a negative regulatory role via affecting NF-B activity.

show abstract

Protein kinase Cδ and protein tyrosine kinase regulate peptidoglycan-induced nuclear factor-κB activation and inducible nitric oxide synthase expression in mouse peritoneal macrophages in vitro

Cited by 30 publications

References 54 publications

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Role of Mitogen-Activated Protein Kinases in Peptidoglycan-Induced Expression of Inducible Nitric Oxide Synthase and Nitric Oxide in Mouse Peritoneal Macrophages: Extracellular Signal-Related Kinase, a Negative Regulator

Contact Info

Product

Resources

About