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The CXC chemokine growth-related oncogene protein-α （GRO-α） has a wide variety of biological activities including as neutrophil trafficking or migration of vascular endothelial cells. In addition, studies have shown a crosstalk between tumor cells and vascular endothelial cells; GRO-α released by endothelial cells induces invasion of tumor cells toward endothelial cells, indicating an importance of GRO-α in a tumor environment. Oral squamous cells are reported to produce GRO-α in response to cytokines such as tumor necrosis factor-α （TNF-α）. However, little is known about how GRO-α is involved in oral cancer. Here, we investigated the biological role of GRO-α for both tumor growth and angiogenesis in oral squamous cell carcinoma cells. We first evaluated the effect of TNF-α on GRO-α expression in three oral cancer cells from different origins. Among the cell lines we used, KOSC-2 cells expressed the highest amount of GRO-α mRNA in response to TNF-α. TNF-α-treated condition medium from KOSC-2 cells enhanced endothelial cell chemotaxis and the chemotactic activity was partially inhibited by the addition of neutralizing anti-GRO-α antibody. In addition, GRO-α exerted tumor cell migration of KOSC-2. From these results, we conclude that GRO-α may contribute to both angiogenesis and proliferation in oral cancer., 弘前医学. 65(2-4), 2014, p.147-155

Viral infection is important in renal pathology both as a trigger of chronic inflammatory diseases and as a complication associated with organ transplantation. Glomerular mesangial cells produce a variety of functional molecules potentially involved in immune reactions, and we investigated anti-viral responses in normal human mesangial cells. Human mesangial cells were treated with polyinosinic-polycytidylic acid （poly IC）, an authentic double-stranded RNA that mimics viral RNA. Treatment of cells with poly IC induced interferon-β （IFN-β）, retinoic acid-inducible gene-I（ RIG-I）, CC chemokine ligand 5（ CCL5）, differentiated embryo-chondrocyte 2（ DEC2） and IFN-stimulated gene 20 （ISG20）. Knockdown of toll-like receptor 3 （TLR3）, by RNA interference （RNAi）, abolished the poly IC-induced expression of these molecules. RNAi against IFN-β inhibited the induction of RIG-I, CCL5 and ISG20, but not of DEC2. Knockdown of RIG-I resulted in the reduced expression of CCL5. RNAi against DEC2 enhanced the poly IC-induced expression of IFN-β, RIG-I and CCL5. Transfection of cells with a poly IC/cationic lipid complex induced IFN-β, RIG-I and ISG20. Knockdown of RIG-I decreased the expression of IFN-β and ISG20 induced by transfection with poly IC/cationic lipid. TLR3 and RIG-I may function as recognition receptors against double-stranded RNA, which induce IFN-β and its downstream IFN-inducible genes. In the signaling elicited by poly IC, the IFN-inducible genes include RIG-I and effector molecules as CCL5 with leukocyte chemotactic activity and ISG20 with exonuclease activity on single-stranded RNA. The poly IC-induced expression of DEC2 is independent on IFN-β and it may control the signaling elicited by double-stranded RNA. The poly IC-inducible molecules may mediate anti-viral innate responses in renal mesangial cells., 弘前医学. 64(Suppl.), 2013, p.S70-73

The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Five clock-gene families, i.e. Clock, Bmal, Per, Cry and Dec, have been found to be involved in a transcription-translation feedback loop that generates the circadian rhythm at the intracellular level. In this study, we examined functional analysis of the Dec gene. DEC1 and DEC2 are basic-helix-loop-helix （bHLH） transcription factors, involved in cellular diff erentiation, responses to hypoxia, and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was upregulated by hypoxia, however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor （VEGF） is upregulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1 α （HIF-1α） and arylhydrocarbon receptor nuclear translocator 1 （ARNT1）. In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1α but not with ARNT1. The binding of HIF-1α to the hypoxia response element（ HRE） in the VEGF promoter was decreased by DEC2 overexpression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved., 弘前医学. 61(Suppl.), 2010, p.S43-S52

Optimization of neuronal function and survival is an important goal in the treatment of cerebrovascular diseases in order to avoid or improve devastating long-term sequelae. Nerve growth factor （NGF） is essential for neuronal growth and survival in the central nervous system （CNS）. Vascular endothelial growth factor （VEGF） is a potent mitogen specifi c for endothelial cells and a stimulator of neovascularization. VEGF also enhances vascular permeability, which may promote the development of brain edema during cerebral ischemia. These molecules aff ect the outcome of ischemia/reperfusion injury in the CNS. Edaravone, a brain-penetrant, free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Transcription factor Nrf2（ nuclear factor-erythroid 2-related factor 2）, a master regulator of antioxidant responses, plays an important role in the coordinated expressions of stress-inducible genes. Astrocytes express various genes involved in the regulation of neuronal functions, and the regulation of astrocyte gene expressions may be a potential therapeutic target in brain injury. This review aims to appraise the eff ects of radical scavenger edaravone and a natural Nrf2-inducer as neuroprotective agents in human astrocytes, particularly under an experimental model for hypoxia/reoxygenation., 弘前医学. 61(Suppl.), 2010, p.S147-S156

The innate and adaptive immune systems have been reported to play an important role in the pathogenesis of glomerular diseases. Since viral infections may trigger the development of inflammatory renal disease or the worsening of preexisting renal disease, recent studies have focused on the involvement of toll-like receptors (TLRs) and their signaling pathways in the inflammatory processes of glomerular cells. Viral double-stranded RNA (dsRNA) can activate not only TLR3 located within intracellular endosomes but also retinoic-acid-inducible-gene-I- (RIG-I-) like helicase receptors located within the cytosol. RIG-I and melanoma differentiation-associated gene 5 (MDA5) are members of the RNA helicase family in the cytosol, and both act as pathogen recognition receptors. The activation of TLRs and their downstream immune responses can be induced by both infectious pathogens and noninfectious stimuli such as endogenous ligands, and this mechanism may be involved in the pathogenesis of autoimmune renal diseases. However, there are few data on the interaction between TLR3, MDA5, and RIG-I in autoimmune glomerular diseases. Based on our recent experimental studies using cultured normal human mesangial cells (MCs), we found that novel TLR3-mediated signaling pathways in MCs may be involved in the pathogenesis of glomerular diseases. In the present paper, we summarize our recent findings.