Rabbit CD200R binds host CD200 but not CD200-like proteins from poxviruses.

CD200 is a widely distributed membrane protein that gives inhibitory signals through its receptor (CD200R) on myeloid cells. CD200 has been acquired by herpesviruses where it has been shown to interact with host CD200R and downmodulate the immune system. It has been hypothesized that poxviruses have acquired CD200; but the potential orthologues show less similarity to their hosts. Myxoma virus M141 protein is a potential CD200 orthologue with a potent immune modulatory function in rabbits. Here, we characterized the rabbit CD200, CD200R and tested the CD200-like sequences for binding CD200R. No binding could be detected using soluble recombinant proteins, full length protein expressed on cells or myxoma virus infected cells. Finally, using knockdown models, we showed that the inhibitory effect of M141 on RAW 264.7 cells upon myxoma virus infection is not due to CD200R. We conclude that the rabbit poxvirus CD200-like proteins cause immunomodulation without utilizing CD200R.

Importance of TNF-related apoptosis-inducing ligand in pathogenesis of interstitial cystitis.

INTRODUCTION: Although interstitial cystitis is an inflammatory disease, its etiopathogenesis is not clearly understood. The objective of the present study is to investigate the distribution of TNF-related apoptosis-inducing ligand (TRAIL) and its receptors in bladder biopsy samples of patients diagnosed with interstitial cystitis and the role of TRAIL in the pathogenesis of interstitial cystitis. MATERIALS AND METHODS: TRAIL and its receptors were stained immunohistochemically in bladder biopsy samples of 27 patients diagnosed with interstitial cystitis, and the samples were evaluated independently by two pathologists and were scored in terms of expression intensity and distribution. RESULTS: An evaluation of the results of the statistical analysis showed that the TRAIL-R4 receptor was immunohistochemically stained with a higher score than TRAIL-R1, TRAIL-R2, TRAIL-R3 receptors and TRAIL, with a statistically significant difference (P < 0.05). CONCLUSION: These findings indicate that TRAIL-R4 is the predominant receptor in the interstitial cystitis inflammation.

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer.

PURPOSE: Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor. EXPERIMENTAL DESIGN: This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2'-O-methyl derivatization for in vivo administration. RESULTS: CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss. IGF1R depletion also enhanced sensitivity to mTOR inhibition, at least in part due to suppression of rapamycin-induced Akt activation. Administration of stabilized IGF1R siRNA was shown to sensitize CC-RCC xenografts to rapamycin in vivo. CONCLUSION: These data validate IGF1R as a therapeutic target in CC-RCC, and support the evaluation of IGF1R-inhibitory drugs in patients with renal cancer.

Tibial nerve stimulation diminishes mast cell infiltration in the bladder wall induced by interstitial cystitis urine.

OBJECTIVES: To investigate whether the urine of interstitial cystitis (IC) patients has a toxic effect on the bladder wall, as determined by mast cell infiltration, and to evaluate the preventive effect of tibial nerve electric stimulation (TNES) on bladder mastocytosis induced by IC urine. MATERIAL AND METHODS: The bladders of female rats were catheterized and instilled with IC urine (Group IC; n=10) and normal urine (Group NU; n=5) obtained from humans, saline (Group S; n=5) and protamine sulphate (Group PS; n=10) for 6 weeks. Additionally, in five rats instilled with IC urine and five instilled with PS, TNES was also performed (Groups IC + TNES and PS + TNES). RESULTS: In the lamina propria of the bladder, the mean number of mast cells per square millimetre was significantly higher in Groups IC (32.5+/-12.3) and PS (39.4+/-11.1) than in Groups S (11.9+/-4.3) and NU (13.7+/-3.5). After TNES, the corresponding values were decreased significantly to 15.3+/-5.4 and 15.3+/-4.1 in Groups IC + TNES and PS + TNES, respectively (p<0.001). A significant reduction in mast cell infiltration in the detrusor was also determined after TNES compared with the value in Group IC (4.6+/-1.6 vs 12.1+/-3.0; p<0.001). CONCLUSIONS: We demonstrated that IC urine may result in increased mast cell infiltration in the bladder wall. TNES may play a therapeutic role by diminishing the mast cell count in the bladder wall, which has a strong relationship with nociceptive neural endings.