SUMMARY Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C. albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, we generated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17raΔK13). Following oral Candida infection, Il17raΔK13 mice exhibited fungal loads and weight loss indistinguishable from Il17ra−/− mice. Susceptibility in Il17raΔK13 mice correlated with expression of the antimicrobial peptide β-defensin 3 (BD3, Defb3). Consistently, Defb3−/− mice were susceptible to OPC. Thus, OECs dominantly control IL-17R-dependent responses to OPC through regulation of BD3expression.

Tumor necrosis factor-␣ (TNF␣)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of prodeath Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNF␣-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNF␣ in the presence of Dgalactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the biddeficient mice. Additional genetic factor(s) could further modify the dependence of TNF␣ toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNF␣-mediated pathogenesis in vivo.

Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/06/16/jimmunol.090373

Originally characterized as a growth factor for erythrocytes, erythropoietin (EPO) is used to treat anemia and fatigue in cancer patients receiving radiation therapy and chemotherapy. EPO and the EPO receptor (EPOR) are expressed in nonhematopoietic cells and cancers. However, the role of EPO and EPOR within nonhematopoietic cancer cells remains incompletely understood. Although a recent clinical trial demonstrated worse tumor control and survival in head and neck cancer patients treated with EPO, the role of EPO and EPOR in head and neck squamous cell carcinoma (HNSCC) has not been examined. In the present study, we demonstrate the previously unrecognized EPO-mediated invasion by HNSCC cells through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Furthermore, we confirmed the expression of EPO and EPOR in a panel of human HNSCC cell lines and tissue specimens. Pharmacological doses of EPO also had a limited proliferation effect in these cell lines. These results define a novel role for EPO in mediating tumor cell invasion. Increased levels of EPO and EPOR in lymph node metastases as compared to primary tumors from HNSCC patients further support the role of EPO/EPOR in HNSCC disease progression and metastasis.