Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. IntroductionDendritic cells (DCs) are thought to be indispensable to initiate primary immune responses and play a pivotal role in linking the innate immunity and the adaptive immunity. 1,2 Their functions directly determine the outcome of T helper (Th) cell-mediated immune responses. 3,4 Normally, DCs reside in almost every tissue where they keep an immature state (imDCs) and serve as sentinels for the "dangerous" antigens. On stimulation with antigens or other signals, they undergo maturation and the matured DCs (mDCs) then migrate to the draining lymph nodes, where they present antigens to naive T cells. 5,6 In addition to their antigen presenting capability executed by the MHC class II molecules and the costimulatory molecules (CD40, CD80, and CD86), DCs also manipulate the nature and extent of the T cell-mediated immune responses through producing a variety of cytokines in response to the TLR ligands. 7 IL-12, which is deemed as a critical signal in T-cell polarization, together with IFN-␥, instructs naive T cell to shift toward a Th1 response, whereas IL-4 and a low level of IL-12 cause a Th2 response. In addition, the generation of regulatory T (Treg) cells requires 5,8,9 Therefore, the tissue environmental factors profoundly influence the adaptive immune responses through their modulation on DCs.Tissue inhibitors of metalloproteinases (TIMPs), specific inhibitors of matrix metalloproteinases (MMPs), consist of a family of 4 proteins that have been characterized so far. Independent of their inhibitory ability on MMPs, they also perform other biologic activities, such as promotion of cell proliferation, proapoptotic and antiapoptotic, and synaptic plasticity activities. 10,11 TIMP-3, a unique member of this family, is mainly sequestered to tissue extracellular matrix and is the only TIMP capable of inhibiting membrane bound MMPs, transmembrane MMPs, and sheddases, such as TNF-␣ converting enzyme. 12,13 TIMP-3 has been shown to act as a tumor suppressor in different cancer types, and loss of TIMP3 is closely associated with acquisition of tumorigenesis. 14-17 TIMP-3 can inhibit invasion and induce cell apoptosis in some specific cancer cell strains. [18][19][20][21][22] These observations indica...

Objectives:To explore the applicability of the current prognostic models for nonmetastatic renal cell carcinoma in the Chinese population based on a single center experience. Methods: Clinical and pathological variables of 653 nonmetastatic renal cell carcinoma patients were retrospectively reviewed. Seven models were used to predict the prognosis, including the Yaycioglu model, the Cindolo model, the University of California Los Angeles Integrated Staging System model, the stage, size, grade, and necrosis model, the Kattan nomogram, the Sorbellini nomogram and the Karakiewicz nomogram. Three different end-points were used for validation, including overall survival, cancer-specific survival, and recurrence-free survival. Survival was estimated using the Kaplan-Meier method. Discriminating ability was assessed using the Harrell's concordance-index. Results: At the last follow up, 159 patients had died due to various causes, and disease recurrence occurred in 156 patients. The discriminating ability of all models was confirmed in the Chinese population. Nomograms discriminate better than algorithms, regardless of end-points. The Kattan nomogram was the most accurate, with the highest concordance-indexes of 0.752, 0.793 and 0.841 for overall survival, cancerspecific survival, and recurrence-free survival, respectively. Conclusions:The current prognostic models were developed and validated entirely based on Caucasian populations. This study defines the general applicability of the models for Chinese patients with nonmetastatic renal cell carcinoma treated with nephrectomy. The Kattan model was found to be the most accurate. The Cindolo model performed well in some situations, although only including clinical presentation and size of tumor. Therefore, models should be chosen according to different environments and purposes.

BBM exhibited strong anti-PCa activities in vitro and in vivo relying on activating caspase-3 via intrinsic pathway of apoptosis, holding a great promise to develop new strategies for PCa.