Text Box: IL-15                                                    

                                          

 Inflammatory diseases

 Rheumatoid arthritis                                                      

 TB

                                                          

Text Box: IFN-gamma                                                   

                                                    

                                                            

                                              

Text Box: Pge2                                                     

                                                                               

                                                    

Proc Natl Acad Sci U S A. 2006 Jun 9; [Epub ahead of print]

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IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-{gamma}, endothelin, and prostaglandin.

Verri WA Jr, Cunha TM, Parada CA, Wei XQ, Ferreira SH, Liew FY, Cunha FQ.

Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirao Preto, Sao Paulo, Brazil; Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow G11 6NT, United Kingdom.

IL-15 is closely associated with inflammatory diseases. IL-15 targeting is effective in treating experimental and clinical rheumatoid arthritis (RA). Because hyperalgesia accompanies RA, we investigated the ability of IL-15 to induced nociceptor sensitization (hypernociception). We report here that IL-15 induced time- and dose-dependent mechanical hypernociception in mice. IL-15-induced hypernociception was inhibited by treatment with a dual endothelin receptor type A (ETA)/endothelin receptor type B (ETB) antagonist (bosentan), ETA receptor antagonist (BQ123), or cyclooxygenase inhibitor (indomethacin). Moreover, IL-15 failed to induce hypernociception in IFN-gamma(-/-) mice, suggesting that IL-15 mediated hypernociception via an IFN-gamma-, endothelin (ET)-, and prostaglandin-dependent pathway. Consistent with this finding, IFN-gamma and ET-1 induced dose- and time-dependent mechanical hypernociception that was inhibited by BQ123 or indomethacin but not BQ788 (an ETB receptor antagonist). IFN-gamma induced the production of ET-1 and the expression of its mRNA precursor (preproET-1, PPET-1). Moreover, IL-15 also induced ET-1 production and PPET-1 mRNA expression in an IFN-gamma-dependent manner. Prostaglandin E2 (PGE2) production was induced by IL-15, IFN-gamma, or ET-1. We also found that hypernociception induced by ovalbumin (OVA) in OVA-immunized mice was significantly diminished by treatment with sIL-15Ralpha (soluble IL-15 receptor alpha-chain), bosentan, BQ123, or indomethacin. Furthermore, OVA challenge induced the expression of PPET-1 mRNA in WT mice but not in IFN-gamma(-/-) mice. The PPET-1 mRNA expression was also inhibited by sIL-15Ralpha pretreatment. Therefore, our results demonstrate the sequential mechanical hypernociceptive effect of IL-15 --> IFN-gamma --> ET-1 --> PGE2 and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception.

PMID: 16766656 [PubMed - as supplied by publisher]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Expression of tyrosine kinase receptors in lung carcinoids.

Granberg D, Wilander E, Oberg K.

Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. Dan.Granberg@medsci.uu.se

OBJECTIVES: Typical lung carcinoids are usually relatively benign tumors, but distant metastases are seen in up to 12% of the patients. In contrast, atypical carcinoids are more aggressive tumors, displaying metastases in up to 70%. The current treatment of metastatic lung carcinoids is discouraging. New therapies, such as inhibitors of the tyrosine kinase receptor family c-kit, platelet-derived growth factor receptors (PDGFR) alpha and beta and epidermal growth factor receptor (EGFR) have shown promising results in other malignancies and might be of value in malignant lung carcinoids. PATIENTS AND METHODS: Tumor tissue from 51 patients with typical lung carcinoids were immunostained with polyclonal antibodies against c-kit, PDGFRalpha, PDGFRbeta and EGFR. Of the 24 patients who had metastatic disease, 17 had distant metastases. Fifteen of the patients had died from their disease. RESULTS: Twelve of the tumors stained positive for c-kit, 44 expressed PDGFRalpha, 30 showed positive immunoreactivity for PDGFRbeta and 26 were EGFR immunoreactive. Among the 17 patients with distant metastases, 5 tumors expressed c-kit, 12 were PDGFRalpha immunoreactive, 9 stained positive for PDGFRbeta, and 7 showed positive immunoreactivity for EGFR. There was no correlation to distant metastases or survival for c-kit, PDGFRbeta or EGFR. CONCLUSIONS: Tyrosine kinase receptors such as c-kit, PDGFRalpha, PDGFRbeta and EGFR are expressed in a significant number of patients with metastatic lung carcinoids. Treatment with inhibitors of the tyrosine kinase receptors expressed may be considered.

PMID: 16612146 [PubMed - indexed for MEDLINE

Clin Otolaryngol. 2006 Jun;31(3):246.

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PTTG promotes a novel VEGF-KDR-ID3 autocrine mitogenic pathway in thyroid cancer.

Kim DS, Buchanan MA, Stratford AL, Watkinson JC, Eggo MC, Franklyn JA, McCabe CJ.

Department of ENT Surgery, University Hospital, Birmingham, UK.

Background. VEGF exerts its effects by binding to tyrosine kinase receptors, KDR and VEGFR1. KDR is critical for transmitting signals for proliferation of endothelial cells but is also expressed in several non-endothelial cells suggesting existence of autocrine stimulatory pathways. Study-design. We investigated VEGF and KDR expression in human thyroid epithelial cells in vitro and thyroid cancers samples ex vivo. Results. Expression of KDR was demonstrated using Taqman RT-PCR and Western blotting in a human follicular thyroid cancer line (FTC133) and primary thyroid epithelial cells. Further, VEGF-specific and dose-dependent activation of KDR-dependent MAPK signalling and KDR-dependent mitogenesis was demonstrated. KDR mRNA expression was elevated in thyroid cancers (2.5-fold, n = 38, P < 0.001), and immunohistochemistry demonstrated stronger phosphorylated-KDR staining in thyroid cancer cells. Further, we showed that PTTG, an oncogene known to promote angiogenesis, up-regulates KDR (2.2-fold, P = 0.006) and VEGF (2.4-fold, P < 0.001) expression in FTC133 thyroid cells. Next, we examined expression of ID3, known to be important in VEGF-dependent angiogenesis, and VEGF mRNA expression in a series of thyroid cancers. We observed a strong positive correlation between expression of these genes (R(2) = 0.62, P < 0.001). Stimulation of FTC133 cells with exogenous VEGF increased ID3 expression (2.1-fold, P < 0.001), an effect abrogated by a KDR-specific inhibitor, suggesting VEGF regulation of ID3 is KDR-dependent. Conclusion. We suggest the presence of a VEGF-KDR-ID3 dependent autocrine pathway in thyroid cells. By up-regulating both VEGF and KDR expression, we propose that PTTG may promote this autocrine proliferative pathway which may in turn be critical to thyroid cancer progression.

PMID: 16759264 [PubMed - in process]