We found a new function of heat shock protein (HSP) that is maintenance of higher order structure of DNA under various stresses conditions in E. coli and predicted that the induction of HSP suppress apoptosis in gastric mucosal cells. We found that various stresses for gastric mucosa, such as ethanol, oxidative stress, acid, and NSAIDs caused apoptosis in guinea pig gastric mucosal cells in vitro. Induction of HSP by pre-treatment of cells with geranylgeranylacetone (GGA), low concentrations of ethanol, and heat shock suppressed these apoptosis.
Gastric mucosal cells have a rapid cell turnover rate in vivo. We found that gastric mucosal cells in culture undergo spontaneous and rapid apoptosis, which may represent the rapid cell turnover cycle of gastric pit cells in vivo. This spontaneous apoptosis was prevented by HSP induction caused by pre-treatment of cells with GGA, low concentrations of ethanol, and heat shock. From these observations, we consider that HSP induction in gastric mucosal cells protects cells from various stresses by inhibiting apoptosis and increasing the number of gastric mucosal cell caused by inhibition of rapid cell turnover cycle in vivo.

抄録全体を表示

The hepatic stellate cells reside in the Disse's space of hepatic sinusoids. They are the center of retinol metabolism in the liver in physiological situation. When liver injuries occur, they undergo activation or transformation and exhibit the characteristic of myofibroblasts in the other organs. Activated stellate cells generate extracel-lular matrix materials, growth factors such as TGF beta, and their contractility in creases the rigidity of sinusoids and disturbs microcirculation. Thus, the activated cells play multiple roles in the development of liver fibrogenesis. PDGF, which derives from local inflammatory sites, is the strongest mitogen for the activated stellate cells whose PDGF receptor beta are fully induced. Besides classical MAP kinase cascade, PI3-kinase-and Akt-dependent signals are found to be essential in the expression of Gl cyclins and the resulting transition to S phase and cell proliferation.

抄録全体を表示

The clinical features of MS in Japanese are said to be characterized by high incidence of optico-spinal MS (OS-MS), although the frequency of it has recently decreased. The term OS-MS is used to describe a subgroup of patients diagnosed with MS, in which the clinically determined lesions are confined to the optic nerves and the spinal cord. The OS-MS is characterized by a female preponderance, a later onset, a higher score of the expanded disability status scale of Kurtzke (EDSS), milder abnormalities on brain MRIs, higher sero-positive rates for some autoantibodies, and higher cell counts and protein levels in the cerebrospinal fluid, compared with conventional MS. The OS-MS is positively associated with HLA-DPB1^*0501 allele, and the HLA prohile are different between OS-MS and conventional MS. Therefore, the OS-MS is immunogenetically as well as clinically a distinct subtype of MS.

抄録全体を表示

Human T-lymphotropic virus type 1 (HTLV-1) is etiologycally associated with not only adult T cell leukemia but also several chronic inflammatory diseases, including bronchopulmonary disorders. To elucidate the pathogenic mechanisms of HTLV-1-associated lung inflammation, we conducted a histopathological and molecular analysis using transgenic mice which bear pX region of this virus. In these mice, accumulations of inflammatory cells, consisting mainly of lymphocytes, were present in peribronchiolar and perivascular areas. The local expression of p 40^tax gene was seen in peribronchiolar and, to lesser extent, perivascular area, wich was well consistent with the distribution of lung lesions. Inflammatory cytokines, including IL-1β, TNF-α and IFN-γ, and several chemokines, such as MCP-1, RANTES, MIP-1 α and IP-10, were detected in the lungs of transgenic mice. Moreover, there was a significant correlation between expression of MCP-1 and that of p 40^tax and the gene expression of the above chemokines, with the exception of MIP-1α, correlated with the severity of histopathological changes in lungs. Considered collectively, these results suggested that p 40^tax synthesis may be involved in the development of lung lesions caused by HTLV-1 through the induction of local production of inflammatory cytokines and chemokines.

抄録全体を表示

Immune modulation in NOD mice was evaluated using hsp 65 of Mycobacterium leprae.
The splenocyte cultures of NOD mice isolated from 6 weeks of age, which shows no or weak insulitis, produced no IFN-γ without hsp 65 stimulation, but produced with hsp 65 stimulation. On the contrary, the splenocyte cultures isolated from 14 weeks, 21 weeks and 28 weeks, which developed heavy insulitis or IDDM, produced high titer of IFN-γ, and if stimulated with hsp 65, the IFN-γ production have been inhibited by producing IL-10. Thus, hsp 65 had a diversity role in immune responses for IFN-γ production. One is inducing role for IFN-γ and another is inducing role for IL-10.
On IL-12 production, the splenocyte cultures isolated from any ages of NOD mice produced IL-12 physiologically, and hsp 65 stimulation inhibited the IL 12 production completely by inducing IL-10.

抄録全体を表示

Adenosine, an endogenous nucleoside, has a plethora of biological actions on a large variety of cells and can modulate the various functions of cells involved in inflammatory responses. On the other hand, production of extracellular matrices is one of the critical functions of fibroblasts. Among various extracellular matrices, hyaluronate (HA) plays important roles in migration, growth and differentiation of a variety of cells during the course of inflammatory reactions and process of wound healing.
In this study, we investigated the expression of adenosine receptor subtypes in human gingival fibroblasts (HGF) and examined the effects of adenosine on the HA production of HGF by utilizing various agonists specific for adenosine receptor subtypes.
Concerning the expression of adenosine receptors, RT-PCR analysis revealed that HGF expressed adenosine receptor A1, A2 a, and A2 b, but not A3 mRNA. Ligation of adenosine receptors by adenosine or adenosine analogue, 2-chlor-oadenosine (2 CADO) and N⁶-cyclopentyladenosine (CPA; A1 adenosine receptor agonist) but not CGS-21680 (A2 a adenosine receptor agonist) induced the expression of HA synthase mRNA, which is responsible for HA production in HGF. These results suggest that intracellular signal (s) via A1 adenosine receptor may play a central role for the upregulation of HA production by activated HGF in inflamed periodontal lesions.
These results provide new evidence for the possible involvement of adenosine in the regulation of extracellular matrix production during the course of inflammatory responses in periodontal tissues.

抄録全体を表示

トリニトロベンゼンスルホン酸と大腸虚血を組み合わせた惹起により, 新規の炎症性腸疾患ラットモデルを作製した.粘膜傷害スコアに依存した活性酸素産生の亢進が認められ, 本モデルの病態には虚血と活性酸素産生が相乗的に作用していた.本モデルに対してレシチン化スーパーオキサイドディスムターゼ (PC-SOD) は粘膜傷害スコアと活性酸素産生を有意に抑制したが, 未修飾SODではこれらに対する抑制効果は認められなかった.PC-SODは炎症性腸疾患に対して有効である可能性が示唆された.

抄録全体を表示

The tissue selectivity of zaltoprofen (ZP) and other non-steroidal anti-inflammatory drugs (NSAIDs), against prostaglandin (PG) biosynthesis on inflammatory site and stomach was investigated from the viewpoint of eyclooxygenase (COX) enzyme, anti-carrageenin-induced edema and ulcerogenic activity. All the drugs tested inhibited COX-1 and COX-2 activities using the refined enzymes in the concentration-dependent manner. The selectivity ratio of CO-1/CG-2 inhibition was the order that ZP (6.56) >etodolac (EL, 3.93) >diclofenac sodium (DF, 1.96) >loxoprofen (SRS-trans-alcohol form) (1.90) >indomethacin (IM, 0.16) . Selectivity for COX-2 of ZP was superior to those of other NSAIDs. The inhibitory effects of ZP, loxoprofen sodium (LP), EL and IM on the PGE₂ content in the carrageenin-air pouch and the PGE₂ release from the gastric ucosa of the same rat were determined. At the doses of NSAIDs which inhibited the PGE₂ biosynthesis at the same degree in the carrageenin-air pouch, ZP hardly inhibited the PGE₂ release from the gastric mucosa. EL and LP inhibited the PGE₂ biosynthesis at the same degree between inflammatory site and gastric mucosa. On the other hand, IM markedly inhibited the PGE₂ release. All NSAIDs tested inhibited the carrageenin-induced edema in the dose-dependent manner, ED₅₀ values of ZP, EL, LP, DF and IM were 2.4, 13.8, 1.9, 6.4 and 3.7 mg/kg, p.o., respectively. On the other hand, ulcerogenic activity (UD₅₀ value) of ZP, EL, LP, DF and INI were 45.3, 12.5, 5.9, 4.1 and 3.3 mg/kg, p.o., respectively. The good correlation between UD₅₀ values and the inhibitory activity of the PG release from the gastric mucosa of NSAIDs was noted.
From these results, it was found that the inhibitory activity of NSAIDs on the PGE₂ release in the stomach correlated well with the selectivity ratio of COX-1/COX-2 inhibition using enzymes and ulcerogenic activity. So, it was suggested that the selectivities for COX-2 of NSAIDs are associated with anti-inflammatory effects and ulcerogenic activity. Also, it was found that ZP has more selectivity for COX-2 and the PG biosynthesis in the inflammatory site compared with other NSAIDs, which were used in the present study. These properties of ZP were seemed to be contributed to the lower ulcerogenic activity on clinical uses.

抄録全体を表示