gammadelta T cells are important contributors to innate immunity against cancer, but their regulatory role in controlling immune responses remains largely unknown. Here we report that a dominant gammadelta1 T cell population among lymphocytes infiltrating breast tumors possessed a potent ability to suppress naive and effector T cell responses and to block the maturation and function of dendritic cells. Adoptive cotransfer experiments demonstrated their in vivo suppressive activity. However, their immunosuppressive activity could be reversed by human Toll-like receptor (TLR) 8 ligands both in vitro and in vivo. siRNA-mediated knockdown experiments revealed that MyD88, TRAF6, IKKalpha IKKbeta, and p38alpha molecules in gammadelta1 cells were required for these cells to respond to TLR8 ligands, whereas TAK1, JNK, and ERK molecules did not appear to be involved in functional regulation. These results provide new insights into the regulatory mechanisms of tumor-specific gammadelta T cells and identify a unique TLR8 signaling pathway linking to their functional regulation.

The nuclear factor-B (NF-B

T cell ͉ thymus ͉ galactosylceramide ͉ bone marrow

The expression of Mullerian inhibiting substance (MIS),Mullerian inhibiting substance (MIS), also known as antiMullerian hormone (AMH), is essential in normal sex differentiation and reproductive function (for a review, see reference 48). Its expression is tightly regulated in tissue-specific and development-specific manners. MIS expression in the testis is restricted to Sertoli cells and is high in fetal-to-prepubertal mice, but it becomes low in pubertal-to-adult mice. Previous studies have suggested that MIS expression is regulated independently by meiotic germ cells (1, 38), androgens (39), and gonadotropins (24), although the factors that govern the complex expression of the MIS gene have not been fully understood. The MIS promoter contains a number of evolutionarily conserved elements, including those for steroidogenic factor 1 (SF-1), Sox9, and GATA-4, and these conserved elements and corresponding transcription factors have been shown to be required for the activation of MIS transcription (11, 43, 53).SF-1, an orphan nuclear receptor, plays an important role in development and differentiation of the endocrine and reproductive systems (for reviews, see references 37 and 41). Molecular studies have revealed that many genes encoding steroidogenic enzymes and regulators of endocrine function are governed by SF-1 for their expression and contain SF-1 response elements within their proximal promoters. In testicular Sertoli cells, SF-1 is required for the expression of MIS (12, 43). Diverse coregulators have been reported to modulate the effect of SF-1 on gene transcription. WT-1 and GATA-4 activate SF-1-mediated MIS expression (34, 51), whereas DAX-1 represses MIS expression (20). Other proteins, such as steroid receptor coactivator 1 (SRC-1) (7), c-Jun (26), and DP103 (35), have also been shown to modulate the transactivation activity of SF-1, although the significance of these interactions remains elusive in terms of reproductive development and function.NF-B is a pivotal transcription factor governing the expression of early response genes involved in numerous cellular responses to a wide range of signals. The major form of NF-B is a heterodimer of the p65 and p50 subunits. In the inactivated state, NF-B is sequestered in the cytoplasm through its association with the inhibitor protein IB. Activation of the NF-B signaling cascade results in phosphorylation and subsequent degradation of IB, allowing the translocation of NF-B to the nucleus, where it induces transcription by binding to specific response elements (4). Previous studies have shown that NF-B cross-talks with other proteins. The NF-B transactivation function is modulated by proteins such as C/EBP, SRC-1, glucocorticoid receptor (GR), and RXR, resulting in the regulation of promoters with B enhancer motifs (31)(32)(33)45). Furthermore, NF-B itself is able to repress the activity of steroid receptors, modulating a number of gene responses to hormonal stimuli (17,31,36).There have been reports of an inverse relationship between

ABSTRACT

Activated monocyte-macrophages have been implicated in tumor angiogenesis via their capacity to produce many potent angiogenic factors. However, the mechanisms leading to production of these angiogenic factors in macrophages remain to be elucidated. In this study, we demonstrated by use of a mouse Matrigel implantation model that mouse peritoneal macrophages induce angiogenesis. mRNA expression and protein synthesis of macrophage-derived crucial angiogenic factors such as IL-1, TNF- § , basic fibroblast growth factor, and vascular endothelial growth factor (VEGF) were blocked by platelet-activating factor (PAF) receptor antagonists. It was also observed that inhibitors of NF-‹ B blocked macrophage production of these angiogenic factors. Gene expression and protein synthesis of the angiogenic factors cited above were also inhibited in I ‹ B § -mutated macrophages. VEGF is the most potent angiogenic factor in macrophage-induced angiogenesis. PAF antagonists or NF-‹ B inhibitors also inhibit the capacity of conditioned medium from LPSstimulated human peripheral blood monocytes to induce sprouting of porcine pulmonary arterial endothelial cells. These data indicate that PAF-induced NF-‹ B activation is a common upstream pathway leading to the production of crucial macrophage-derived angiogenic factors. This will provide an important clue for a better understanding of mechanisms involved in tumor angiogenesis.

No abstract

In this study, we investigated the influence of plateletactivating factor (PAF) on the induction of apoptosisregulating factors in B16F10 melanoma cells. PAF increased the expression of mRNA and the protein synthesis of antiapoptotic factors, such as Bcl-2 and Bcl-xL, but did not increase the expression of the proapoptotic factor, Bax. A selective nuclear factor-KB (NF-KB) inhibitor, parthenolide, inhibited the effects of PAF. Furthermore, PAF inhibited etoposide-induced increases in caspase-3, caspase-8, and caspase-9 activities, as well as cell death. p50/p65 heterodimer increased the mRNA expression of Bcl-2 and Bcl-xL and decreased etoposide-induced caspase activities and cell death.In an in vivo model in which Matrigel was injected s.c., PAF augmented the growth of B16F10 cells and attenuated etoposide-induced inhibition of B16F10 cells growth. These data indicate that PAF induces up-regulation of antiapoptotic factors in a NF-KB-dependent manner in a melanoma cell line, therefore suggesting that PAF may diminish the cytotoxic effect of chemotherapeutic agents. (Cancer Res 2006; 66(9): 4681-6)