Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Koon, Hon–Wai; Zhao, Dan; Zhan, Yanai; Rhee, Sang Hoon; Moyer, Mary Pat; Pothoulakis, Charalabos

doi:10.4049/jimmunol.176.8.5050

Cited by 91 publications

(77 citation statements)

References 56 publications

(68 reference statements)

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“…It may play a role in JAK2 activation by IL-6, and this suggestion is supported by a previous report showing that rottlerin reduced the activation of JAK2 in NCM460-NK-1R cells [35]. However, we did not find any difference in JAK2 phosphorylation in the presence or absence of rottlerin (data not shown).…”

Section: Discussionsupporting

confidence: 91%

Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells

2010

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Aims/hypothesis The aim of the study was to address the role of protein kinase C-δ (PKCδ) on phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activation of inflammatory genes in response to IL-6 in adipose cells. Methods Differentiated mouse 3T3-L1 adipocytes preincubated with the PKCδ inhibitor rottlerin and mouse embryonic fibroblasts (MEFs) lacking PKCδ were incubated with IL-6 and/or insulin. RNA was extracted and the gene expression was analysed by real-time PCR, while the proteins from total, nuclear and cytoplasmic lysates were analysed by immunoblotting. Results Inhibition of PKCδ by rottlerin significantly reduced both Ser-727 and Tyr-705 phosphorylation of STAT3. Consequently, nuclear translocation of STAT3 and the IL-6-induced gene transcription and protein release of the inflammatory molecule serum amyloid A 3 (SAA3) were reduced. Similarly, the IL-6-regulated gene transcription of Il-6 (also known as Il6) to Hp and the feedback inhibitor of IL-6, Socs3, were also attenuated by rottlerin. Furthermore, PKCδ was found to translocate to the nucleus following IL-6 treatment and this was also reduced by rottlerin. In agreement with the effect of rottlerin, Pkcδ (also known as Prkcd) −/− MEFs also displayed a markedly reduced ability of IL-6 to activate the transcription of Saa3, Hp, Socs3 and Il6 genes compared with wild-type MEFs. These results correlated with a reduced nuclear translocation and phosphorylation of STAT3. Conclusions/interpretation These results show that PKCδ plays a key role in the inflammatory effect of IL-6 in adipose cells and may be a suitable target for novel antiinflammatory agents.

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Section: Discussionsupporting

confidence: 91%

Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells

2010

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“…The discrepancy may be due to the difference between two different cell types. Another independent pathway, JAK signaling which activates Stat3, has been shown to be involved in COX-2 expression [47]. Our studies also indicate that JAK signaling may participate in TP-mediated COX-2 expression.…”

Section: Discussionsupporting

confidence: 61%

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

Wei

Yan

et al. 2007

Biochemical Pharmacology

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Human lung adenocarcinoma A549 cells stably transfected with TPα (A549-TPα) were used to study agonist I-BOP-induced expression of cyclooxygenase-2 (COX-2) and the related mechanisms of induced expression. I-BOP, a TP agonist, induced a time and dose dependent expression of COX-2 in A549-TPα cells as revealed by Western blot and by the synthesis of PGE 2 and TXB 2 which was totally inhibited by COX-2 inhibitors. The signaling pathways of I-BOP-induced COX-2 expression were elucidated by using various inhibitors of the signaling molecules. The effects of these inhibitors were assessed at three different levels of COX-2 expression: protein, enzyme activity and promoter activity. Within MAPK family, both ERK and p38 MAPK but not JNK/SAPK pathways were involved in the induction. Other pathways such as JAK/Stat3 pathway and β-catenin/TCF/LEF pathway also participated in the induction. The activation of key signaling molecules, ERK, p38 MAPK, CREB and NF-κB, involved in the COX-2 transcription was further studied at the phosphorylation step. Activation of ERK and p38 MAPK appeared to be mediated primarily by transactivation of EGFR, whereas activation of CREB and NF-κB was mediated by PKA, PKC and ERK. The role of CREB and NF-κB in I-BOP-induced COX-2 expression was further explored at the COX-2 promoter level. Studies on promoter fragments of different length and mutation of responsive motifs indicated that CRE and NF-κB sites are critical for the COX-2 induction. Distal NF-κB site is essential for the basal induction of the COX-2 transcription, whereas CRE and proximal NF-κB sites are important for the induced transcription. These results indicate that I-BOP induced COX-2 expression through multiple signaling pathways leading to the activation of CREB and NF-κB transcriptional factors and subsequent COX-2 transcription.

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“…We previously showed that SP-NK-1R interactions lead to Jak2 phosphorylation (27). Previous results also indicate that the signaling molecule PI3K is upstream of Akt signaling (28).…”

Section: Resultsmentioning

confidence: 99%

“…We also present evidence that Jak2 upstream of Akt is involved in this SP response. Interestingly, Jak2 was recently shown to also mediate cyclooxygenase 2 (COX-2) gene up-regulation and prostaglandin E 2 release in human colonocytes exposed to SP (27) and evidence was presented indicating that COX-2 promotes intestinal inflammatory responses (39). Thus, SP-induced Jak2 phosphorylation may mediate both proinflammatory and antiapoptotic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Koon

Zhao

Zhan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

100

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We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells. For the in vitro experiments, human nontransformed NCM460 colonocytes stably transfected with NK-1R (NCM460-NK-1R cells) were exposed to SP, and cell viability assays, TUNEL assays, and Western blot analyses were used to detect apoptotic and antiapoptotic pathways. SP exposure of NCM460-NK-1R colonocytes stimulated phosphorylation of the antiapoptotic molecule Akt and inhibited tamoxifeninduced cell death and apoptosis evaluated by the cell viability assay and poly(ADP-ribose) polymerase cleavage, respectively. SP-induced phosphorylation of Akt and cleavage of poly(ADPribose) polymerase were inhibited by blockade of integrin ␣V␤3, Jak2, and activation of phosphatidylinositol 3-kinase. For the in vivo experiments, C57BL/6 mice, administered 5% dextran sulfate (DSS) dissolved in tap water for 5 days followed by a 5-day recovery period, were treated with the NK-1R antagonist CJ-12,255 or vehicle. Vehicle-treated mice showed increased colonic Akt phosphorylation and apoptosis compared with mice that received no DSS. In contrast, daily i.p. administration of CJ-12,255 for 5 days post-DSS suppressed Akt activation, exacerbated colitis, and enhanced apoptosis, and pharmacologic inhibition of Akt, either alone or together with CJ-12,255, produced a similar effect. Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.apoptosis ͉ colitis

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Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Cited by 91 publications

References 56 publications

Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells

Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

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