Triggering receptor expressed on myeloid cells(TREM)-1 is a cell surface molecule that has been identified on monocytes and neutrophils and is implicated in the early inflammatory response induced by microbes. However, it has been remained unclear how the expression of TREM-1 is regulated in non-microbial inflammatory diseases. This study was undertaken to evaluate the biologic role of TREM-1 in the initiation of acute attacks of gout. We investigated TREM-1 expression by monosodium urate monohydrate(MSU) crystal-stimulated resident murine peritoneal macrophages(RPM), and assessed whether TREM-1 signaling amplified response to MSU crystals. TREM-1 expression by RPM stimulated with various inflammatory agents was determined by quantitative real-time PCR and western blot analysis. Cytokine production by RPM cultured with both anti-TREM-1 agonist antibody and MSU crystals was assayed by ELISA. TREM-1 expression was significantly induced in RPM by MSU crystals. The peaks of TREM-1 transcript and product occurred rapidly after 1 and 4 hours of MSU crystal stimulation, respectively. The level of TREM-1 transcript induced was consistent with the result obtained using LPS, a potent TREM-1 inducer. Induction of TREM-1 by anti-TREM-1 agonist Ab and MSU crystals synergistically increased production of IL-1 β and MCP-1 by RPM compared with MSU crystals alone. These findings indicate that rapid induction of TREM-1 expression in RPM by MSU crystals may contribute to the onset of acute gouty arthritis, followed by induction of proinflammatory cytokines.

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Objective: To study the role of the transcription factor hypoxia inducible factor (HIF)-1α in chondrocyte viability as a cell survival factor during the progression of OA.
Methods: The expression of HIF-1α was histologically investigated in human OA cartilage samples. We studied whether IL-1β induces the expression of HIF-1α in OA chondrocytes under normoxic and hypoxic conditions. Also, we examined the levels of energy generation, and cartilage-matrix production in HIF-1α-deficient chondrocytes.
Results: In articular cartilages from human OA patients, the amount of HIF-1α correlated with the degree of cartilage degeneration. IL-1β up-regulated mRNA and protein levels of HIF-1α in cultured chondrocytes. HIF-1α-deficient chondrocytes did not maintain the energy generation under both normoxic and hypoxic conditions. HIF-1α-deficient chondrocytes showed an acceleration of catabolic stress-induced apoptosis.
Conclusion: Our results in human OA cartilage and in an OA rat model suggest that HIF-1α expression in OA cartilage is closely associated with the progression of articular cartilage degeneration. Catabolic-stresses may accelerate the HIF-1α expression in chondrocytes, suggesting an important role for HIF-1α in the chondrocyte activity in OA articular cartilage.

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Early-onset sarcoidosis (EOS) is juvenile-onset systemic granulomatosis that mainly affects skin, joints and eyes. Recent discovery of NOD2 mutations in the familial systemic granulomatosis, Blau syndrome, encouraged us to investigate NOD2 mutations in EOS patients reported in Japan. Among 10 cases, heterozygous missense mutations were found in 9 cases; 4 showed R334W that has been typically reported in Blau syndrome, and 5 showed novel H496L, M513T, T605P, N670K, and D382E. All these 6 variants of NOD2 showed increased nuclear factor(NF)-kappaB activity without its ligand, such as muramyl dipeptide. These findings indicate that the majority of EOS cases reported in Japan shows the genetic etiology of NOD2 mutations that cause constitutive NF-kappaB activation.

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The primitive roles of neutrophils are known as phagocyte to engulf and kill microorganisms which invade human bodies. Recently, it is well established that neutrophils play important roles to modulate inflammation. Clearance of apoptotic neutrophils by cells such as macrophages can lead to the resolution of inflammation. It is also important to clarify the mechanisms of neutrophilic inflammation and to develop therapeutic strategies based on the induction of neutrophil apoptosis in order to reverse or attenuate an inflammatory response. Several modulators of neutrophil apoptosis and activators of neutrophil priming have been discovered, they have been discussed in the pathogenesis of several diseases. However, we have no potential therapeutic strategy on the property so far. New clinical perspectives in future are expected.

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Cyclooxygenase(COX)-2 has been reported to play an important role in carcinogenesis. Meloxicam (preferential COX-2 inhibitor) inhibits the growth of COX-2 expressing and COX-1 negative colorectal cancer cells. We evaluated the effects of meloxicam on the growth of lung cancer. By reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, COX-2 but not COX-1 was expressed in human non-small cell lung cancer (NSCLC) cell lines (A549 and PC14). In human small cell lung cancer (SCLC) cell line (H841), both COX-1 and COX-2 were not detected. MTT assay and prostaglandin (PG) E₂ enzyme immunoassay showed that meloxicam inhibited the growth and PGE₂ production of both A549 and PC14 but not H841 cells. These findings suggest that COX-2 may play an important role in the pathogenesis and progression of NSCLC and that meloxicam may be a useful therapeutic agent in the treatment of NSCLC.

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Adenosine (Ado) has various biological effects on human gingival fibroblasts (HGF) and epithelial cells, that are closely associated with inflammation. However, little is known regarding mechanisms by which Ado action is regulated. In this study we examined the involvement of CD73 and ecto-adenosine deaminase (ADA) in metabolizing Ado and thus regulating AdoR activation in HGF. Adenosine production was observed following the addition of 5'-AMP, a substrate of CD73-associated ecto-5'-nucleotidase. Moreover, addition of 5'-AMP to HGF resulted in the elevation of cyclic adenosine monophosphate (cAMP). Flow cytometric analysis revealed that ecto-ADA expression on HGF could be increased by pretreatment with exogenous ADA. However, this maximum expression of ecto-ADA did not lead to a significant increase in metabolism of exogenously added extracellular Ado. Interestingly, however, the cAMP response to Ado generated from 5'-AMP via CD73 was significantly decreased by the pretreatment of HGF with exogenous ADA and this inhibitory effect was reversed by the specific ADA inihibitor 2'-deoxycoformycin. These results suggest that ecto-ADA, which can be anchored to CD26 on HGF, has the potential to metabolize CD73-generated Ado in the microenvironmental milieu and that this plays a critical role in the regulation of AdoR activation.

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Mechanical stress has profound influences on human body. Muscle training strengthens the muscles, and high blood pressure thickens the vessel walls. Intense studies have been made by various investigators on how mechanical stress influences the human tissues. Epidermal keratinocytes are continuously exposed to mechanical forces. The human skin surface can be thickened and enlarged by various stress such as tissue expander or abrasive pressure. Keratinocytes were plated on flexible silicone dishes, and they were continuously stretched. Stretching of keratinocytes caused up-regulation of 5-bromo-2'-deoxyuridine (BrdU)-positive cells and activation of extracellular signal-regulated kinases (ERK) 1/2. EGF receptor, calcium channel, and ERK were involved in stretch-induced BrdU incorporation. Stretching also induced keratin K6, which is expressed in activated and proliferating keratinocytes, and suppressed keratin K10, which is expressed in differentiated keratinocytes, and their regulation was inhibited by MEK1/2 inhibitor. EGF receptor as well as adhesion molecules have been reported to be involved in transducing mechanical stresses. Several diseases involving heart and palmoplantar skin are caused by the mutation in desmosomal proteins, indicating that adhesion molecules play an important part in sustaining normal structure of skin under the mechanical stress.

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