Inflammatory diseases
Rheumatoid arthritis
TB
Proc
Natl Acad Sci U S A. 2006 Jun 9; [Epub
ahead of print] Expression of tyrosine kinase
receptors in lung carcinoids. Clin Otolaryngol. 2006
Jun;31(3):246.
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]
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
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]