TNF Receptor-Associated Factor 5 Limits IL-27 Receptor Signaling in CD4+ T Lymphocytes.

TNF receptor-associated factor 5 (TRAF5) restrains early signaling activity of the IL-6 receptor in naive CD4+ T cells by interacting with the shared gp130 chain, although TRAF5 was initially discovered as a cytoplasmic adaptor protein to activate signaling mediated by TNF receptor family molecules. This leads to the question of whether TRAF5 limits signaling via the receptor for IL-27, which is composed of gp130 and WSX-1. The aim of this study is to clarify the role of TRAF5 in IL-27 receptor signaling and to understand the differential role of TRAF5 on cytokine receptor signaling. We found that Traf5 -/- CD4+ T cells displayed significantly higher levels of phosphorylated STAT1 and STAT-regulated genes Socs3 and Tbx21, as early as 1 h after IL-27 exposure when compared with Traf5 +/+ CD4+ T cells. Upon IL-27 and TCR signals, the Traf5 deficiency significantly increased the induction of IL-10 and promoted the proliferation of CD4+ T cells. Traf5 -/- mice injected with IL-27 displayed significantly enhanced delayed-type hypersensitivity responses, demonstrating that TRAF5 works as a negative regulator for IL-27 receptor signaling. In contrast, IL-2 and proliferation mediated by glucocorticoid-induced TNF receptor-related protein (GITR) and TCR signals were significantly decreased in Traf5 -/- CD4+ T cells, confirming that TRAF5 works as a positive regulator for cosignaling via GITR. Collectively, our results demonstrate that TRAF5 reciprocally controls signals mediated by the IL-27 receptor and GITR in CD4+ T cells and suggest that the regulatory activity of TRAF5 in gp130 is distinct from that in TNF receptor family molecules in a T cell.

Complementary Relation Between the Improvement of Dose Delivery Technique and PTV Margin Reduction in Dose-Escalated Radiation Therapy for Prostate Cancer.

PURPOSE: The purpose of this study is to demonstrate quantitatively the complementary relationship between the introduction of intensity modulated radiation therapy (IMRT) and planning target volume (PTV) margin reduction with an image guided technique in reducing the risk of rectal toxicity in dose-escalating prostate radiation therapy. METHODS AND MATERIALS: Three-dimensional conformal radiation therapy (CRT) and IMRT plans were generated for 10 patients with prostate cancer based on 2 PTV margin protocols (10/8 mm and 6/5 mm) and 2 dose prescriptions (70 Gy and 78 Gy). The normal tissue complication probability (NTCP) for each of the 8 scenarios was calculated using the Lyman-Kutcher-Burman model to estimate the risk of rectal and bladder late toxicity. The conformity and homogeneity indices of PTVs were calculated for each plan. RESULTS: The IMRT plans showed superiority in conformity and inferiority in homogeneity over 3-dimensional CRT plans. The rectal NTCPs were increased 3.5 to 4.1 times when the prescribed total dose was changed from 70 Gy to 78 Gy and the dose delivery and the image guided radiation therapy techniques remained unchanged. PTV margin reduction was shown to reduce the value of rectal NTCP significantly. Overall, implementing the IMRT technique alone could reduce the NTCP values only by 2.1% to 7.3% from those of 3-dimensional CRT. The introduction of both IMRT and PTV margin reduction was found to be necessary for rectal NTCP to remain <5% in the dose escalation from 70 to 78 Gy. CONCLUSIONS: The complementary relationship between the introduction of IMRT and PTV margin reduction was proven. We found that both approaches need to be implemented to safely deliver a curative dose in dose-escalating prostate radiation therapy.