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H Mizuhara,
M Kuno,
N Seki,
W G Yu,
M Yamaoka,
M Yamashita,
T Ogawa,
K Kaneda,
T Fujii, H Senoh,
H Fujiwara
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ABSTRACT: A single intravenous injection of concanavalin A (Con A) induces T-cell activation-associated inflammatory injury selectively in the liver. This study investigated the strain difference in the development of Con A-induced hepatic injury. Normal C57BL/6 and BALB/c spleen cells produced comparable levels of T-cell-derived lymphokines (interferon gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-2 [IL-2]) following in vitro stimulation with Con A. A single intravenous injection of Con A to C57BL/6 mice induced the plasma levels of TNF-alpha and IL-2 comparable with or slightly higher than those observed in BALB/c mice, whereas the same treatment resulted in an apparently lower level of IFN-gamma production in C57BL/6 mice. RNA from livers of Con A-treated C57BL/6 mice exhibited lower levels of IFN-gamma mRNA than RNA of BALB/c livers. Unexpectedly, a dramatic difference in the severity of hepatic injury was observed between C57BL/6 and BALB/c. Namely, the peak alanine transaminase (ALT) level was more than 15,000 U/L and inducible as early as 8 hours after injection of 0.2 mg Con A per mouse in the C57BL/6 strain, whereas the peak was approximately 3,000 U/L and induced as late as 24 hours after Con A injection in the BALB/c strain. The increase in plasma ALT levels was limited to less than 10% by injection of anti-IFN-gamma monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of IFN-gamma exhibited higher IFN-gamma responsiveness as exemplified by the intrahepatic expression of an IFN-gamma-inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN-gamma produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN-gamma-dependent hepatic injury.
Hepatology 03/1998; 27(2):513-9. · 11.66 Impact Factor
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ABSTRACT: A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon gamma (IFN-gamma) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-gamma, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-gamma levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN-gamma levels were detected for a more prolonged period. Passive immunization with anti-IFN-gamma monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-gamma MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-gamma and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-gamma MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-gamma MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN-gamma plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-gamma.
Hepatology 07/1996; 23(6):1608-15. · 11.66 Impact Factor
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ABSTRACT: This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rIL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rIL-6; and (c) rIL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.
Journal of Experimental Medicine 05/1994; 179(5):1529-37. · 13.85 Impact Factor
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ABSTRACT: We examined the effects of adenosine analogues on the asthmatic reactions induced by the stimulation of capsaicin-sensitive afferent sensory nerves. Intravenous (i.v.) injection of adenosine A2 receptor agonists, 5'-(N-ethylcarboxamido)-adenosine (NECA) and 2-[p-(carboxyethyl)-phenylethylamino]-5'-N-ethylcarboxamido-adenos ine (CGS 21,680), dose dependently inhibited capsaicin-induced guinea-pig bronchoconstriction (1-1000 nmol kg-1), whereas i.v. administration of the adenosine A1 receptor agonist, N6-cyclo-hexyladenosine (CHA), did not affect it (1000 nmol kg-1). Intratracheal injection of NECA (0.05-5 nmol site-1) and CGS 21,680 (0.05-5 nmol site-1) also reduced capsaicin-induced constriction in a dose-dependent manner. However, NECA (1000 nmol kg-1) failed to inhibit substance P-induced guinea-pig bronchoconstriction. NECA (1-1000 nmol kg-1) dose-dependently inhibited cigarette smoke-induced rat tracheal plasma extravasation, but not substance P-induced reaction. NECA (0.1-10 microM) and CGS 21,680 (10 microM) significantly blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea-pig lung, whereas CHA (10 microM) had no effect. This evidence suggests that adenosine A2 receptors modulate negatively the excitation of capsaicin-sensitive afferent sensory nerves and substance P release from their endings in airway tissues.
European Journal of Pharmacology 09/1993; 240(2-3):121-6. · 2.52 Impact Factor
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ABSTRACT: Two sets of ((resistant x susceptible) F1----parent) and (parent----F1) chimeric mice were prepared. In the chimeric combinations involving BALB/c and DBA/1 mice, all (F1----F1) chimeras developed arthritis as well as potent anticollagen responses after immunization with collagen, whereas all (F1----BALB/c) and (BALB/c----F1) chimeras induced neither arthritis nor immune responses. This type of F1 T cells could be activated with APC from DBA/1 but not from BALB/c mice. Thus, the failure of the [F1 in equilibrium with BALB/c] chimeras to mount anticollagen responses was due to a defect at the APC level. Another arthritis-resistant strain, C57BL/6, exhibited adequate APC function, but reduced T cell responsiveness, representing an intermediate responder. In the chimeric combinations involving C57BL/6 and DBA/1 mice, (F1----F1) and (C57BL/6----C57BL/6) chimeras developed very high and very low incidence of arthritis, respectively. (C57BL/6----F1) chimeras developed an appreciable incidence of arthritis under conditions in which this group of chimeras generated intermediate levels of anticollagen responses. In contrast, (F1----C57BL/6) chimeras developed low incidence of disease despite induction of strong responses. Moreover, cells from collagen-immunized (F1----C57BL/6) chimeras, when transferred into T cell-depleted B cell mice of F1 or C57BL/6 strain, produced comparable immune responses in both groups but induced much more severe arthritis in F1 than in C57BL/6 recipients. These results indicate that: i) two types of arthritis-resistant strains can be identified, each of which has anticollagen APC defect as a low responder and reduced T cell responsiveness as an intermediate responder and ii) a discrepancy between the degree of anticollagen responses and clinical arthritis is attributed to the differential susceptibility to anticollagen immune responses.
The Journal of Immunology 06/1992; 148(10):3093-9. · 5.79 Impact Factor
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ABSTRACT: We established an interleukin-6 (IL-6)-dependent cell line from murine plasmacytoma MOPC-104E cells. This cell line (designated PIL-6) was found to respond to murine and to human IL-6, but not to any other cytokines. We used this cell line to investigate the involvement of IL-6 production in type II collagen-induced arthritis in DBA/1 mice. Only marginal IL-6 activity was detected in sera from DBA/1 mice inoculated with Freund's complete adjuvant (FCA) alone, with an unrelated protein (bovine serum albumin) plus FCA, or with type II collagen plus Freund's incomplete adjuvant. However, enhanced IL-6 activity was observed in DBA/1 mice that had been injected with type II collagen plus FCA to induce arthritis. The elevated level of serum IL-6 activity was associated with high levels of IL-6 produced when lymph node cells from arthritic mice were stimulated in vitro with type II collagen. We also found that the L3T4+ T cell subset is responsible for the enhanced production of IL-6 in arthritic mice. The results are discussed in the context of potential roles of IL-6 in the induction and/or expression of chronic, progressive arthritis.
Arthritis & Rheumatism 06/1989; 32(5):594-600. · 7.87 Impact Factor
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ABSTRACT: The plasma extravasation inducing activities of several chemical mediators (allergic agents: histamine, leukotriene C4 (LTC4) and platelet activating factor (PAF); neurogenic agents: substance P, capsaicin and carbachol) have been investigated and characterized in rat skin and trachea. Substance P, histamine, LTC4 and PAF induced dose-dependent plasma extravasation in rat skin. The activities of these mediators in inducing tracheal plasma extravasation were very different from those in the skin reactions. When these mediators were injected intravenously, substance P induced severe plasma extravasation, and the activities of histamine and PAF were weaker than that of substance P. When injected intratracheally, only substance P and capsaicin induced tracheal plasma extravasation, while none of the allergic mediators tested caused any plasma extravasation in the trachea. Carbachol did not induce any plasma extravasation in either skin or trachea. These results indicate that the stimulation of afferent substance P-containing nerve fibers has a more important role in the induction of tracheal plasma extravasation than that of allergic chemical mediators.
The Japanese Journal of Pharmacology 04/1989; 49(3):389-95.
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ABSTRACT: Immunization of DBA/1 mice with type II collagen resulted in typical and progressive arthritis, which is associated with the production of high titer of anti-collagen antibody and the induction of cell-mediated immunity as exemplified by delayed type hypersensitivity response as well as lymphokine production. In contrast, administration of heat-denatured collagen into DBA/1 mice failed to induce the arthritis. These mice produced only marginal antibody, whereas they developed comparable cell-mediated immunity to that induced by immunization with native collagen, and therefore the inoculation of heat-denatured collagen provided the regimen capable of inducing preferentially cell-mediated immunity without the generation of high level of antibody. Inasmuch as administration of antibody induced only marginal and transient joint swelling not associated with typical histologic lesion, the synergistic effect of humoral and cell-mediated immunities was investigated using antibody preparation and the regimen to induce selectively cell-mediated immunity. The results demonstrate that administration of antibody into DBA/1 mice pre-sensitized with heat-denatured collagen resulted in potent and progressive arthritis. Such synergy was further confirmed by the induction of arthritis in T cell-depleted DBA/1 mice that had been adoptively transferred with antibody and lymphoid cells from heat-denatured collagen-sensitized mice. Moreover, it was revealed that the nature of cells capable of transferring cell-mediated immunity was of Thy-1+ and L3T4+ Lyt-2-. These results indicate that anti-collagen antibody and L3T4+ T cell-mediated cellular immunity are crucially required for the perpetuated development of type II collagen-induced arthritis.
The Journal of Immunology 04/1988; 140(5):1477-84. · 5.79 Impact Factor
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ABSTRACT: The mode of action of Nocardia rubra cell wall skeleton (N-CWS) on Meth A fibrosarcoma (Meth A) was studied in BALB/c mice. N-CWS suppressed or regressed the intradermal growth of syngeneic Meth A cells in normal BALB/c and athymic BALB/c mice. The intradermally and subcutaneously infiltrated cells harvested from injection sites of N-CWS in normal mice showed in vitro cytotoxic activity against Meth A cells. Pretreatment of normal BALB/c mice with immunosuppressing agents such as hydrocortisone, carrageenan, or silica particles significantly reduced the anti-tumor effect of N-CWS. The growth of Meth A cells, rechallenged into BALB/c mice in which Meth A cells had once been suppressed or regressed by N-CWS treatment, was also inhibited, but not in similarly treated athymic nude mice. This resistant mechanism was shown to be dependent out cellular components but not on humoral components by the Winn Assay. The present results suggest that N-CWS exerts its anti-tumor activity by mediation of the immune system of the host and that the main effector cells in the early stage of tumor rejection are macrophages; T cells may also be involved in the later stage.
Folia Pharmacologica Japonica 05/1987; 89(5):307-16.
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ABSTRACT: The effect of an oral gold preparation, auranofin, on the autoimmune disease mouse MRL/l was examined. Oral administration of auranofin on consecutive days from 6 weeks of age reduced anti-DNA antibody production, IgM rheumatoid factor production, hypergammaglobulinemia, polyclonal B cell activation and renal disease, but did not prevent massive lymphadenopathy or restore the low level of either IL-2 production or mitogen response associated with 1pr gene. In contrast to the effect on autoantibody production, little suppressive activity on the immune response to exogenous antigen SRBC was observed. These results indicate that autoimmune disease in MRL/l mice can be prevented without abrogation of T cell abnormalities and that autoimmune-selective suppression can be induced by chemical compound(s) like auranofin.
International Journal of Immunopharmacology 01/1986; 8(8):897-910.
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ABSTRACT: The anti-inflammatory effects of auranofin were studied and compared with those of indomethacin, gold sodium thiomalate (GST) and D-penicillamine. Auranofin was active as indomethacin in inhibiting carrageenan induced paw edema in rats, but was less potent than indomethacin in inhibiting UV-induced erythema in guinea pigs. Auranofin inhibited Arthus type paw edema and reverse PCA reaction in rats, on which indomethacin was ineffective. The inhibitory activity of auranofin on adjuvant arthritis was weaker than that of indomethacin. In in vitro experiments, auranofin did not show any suppression of cyclooxygenase activity, but was capable of suppression of lysosomal enzyme release and chemotaxis of neutrophils and macrophages. In addition to these anti-inflammatory activities, auranofin had almost equal anti-analgesic and anti-pyretic activity to that of indomethacin. The above results indicated that the anti-inflammatory profiles of auranofin and indomethacin differ, so we can expect new therapeutic activities of auranofin. GST had similar anti-inflammatory and anti-analgesic profiles to those of auranofin; however, the activities were less potent than auranofin and devoid of anti-pyretic activity. D-penicillamine did not show any anti-inflammatory, anti-analgesic or anti-pyretic activity.
Folia Pharmacologica Japonica 01/1986; 86(6):441-55.
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ABSTRACT: The systemic and topical antiinflammatory activities of budesonide (B) were studied in rats and mice and compared with those of commercially available steroids. Betamethasone 17-valerate (BV) was used as the main reference compound, and fluosinolone acetonide (FA), hydrocortisone 17-butyrate (HB) and hydrocortisone 21-acetate (HA) were also used. B given systemically had stronger antiinflammatory effect than BV on carrageenin edema, cotton pellet granuloma, adjuvant arthritis, croton oil edema, PCA reaction, Arthus reaction, contact hypersensitivity and histamine or serotonin skin reaction. The potency of antiinflammatory activity of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was in the order of FA, B, BV, HB and HA. B given locally also produced stronger antiinflammatory effects than BV on carrageenin edema, cotton pellet granuloma, croton oil edema and contact hypersensitivity. The order of potency of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was the same as by systemic application. In general, the ratio of the dose required to cause atrophy of the thymus and adrenals to the dose required to produce the antiinflammatory effect was the greatest with B by both systemic and local application. The results suggest that B has a stronger antiinflammatory activity with fewer systemic side effects than conventional steroid compounds.
Folia Pharmacologica Japonica 10/1985; 86(3):219-31.
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ABSTRACT: The antiinflammatory effect of topically applied budesonide ointment on carrageenin induced paw edema in rats, croton oil induced ear edema in rats, passive cutaneous anaphylaxis (PCA) in rats and picrylchloride induced contact hypersensitivity in mice was studied and compared with those of commercially available ointments containing betamethasone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 17-butyrate or fluocinonide. The five ointments had almost the same degree of activity against the carrageenin induced paw edema. Budesonide ointment was strongest in inhibiting the croton oil induced ear edema. Budesonide and fluocinonide ointments were stronger than the other 3 ointments in inhibiting PCA and picrylchloride induced hypersensitivity. No clear atrophic effect on the thymus or adrenal was observed with any of the ointments at the doses tested. When the effect of budesonide ointment was compared with that of budesonide cream, there were no differences in activity between the two formulations. The results suggest that budesonide is a useful drug with a superior topical antiinflammatory activity.
Folia Pharmacologica Japonica 10/1985; 86(3):233-9.
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ABSTRACT: The present study investigates the cellular and molecular mechanisms responsible for expressing genetic control of type II collagen-induced murine chronic arthritis. Analyses were made for both humoral and cellular immune responses, since the induction of arthritis required synergy between both types of immunities. Immunization of high (DBA/1) and low (C57BL/6, C3H/He, BALB/c) responder mice with native bovine type II collagen resulted in the production of the respective high and low levels of anti-collagen antibody. However, polyclonal in vitro stimulation of normal spleen cells from high or low responder mice with lipopolysaccharide (LPS) induced a comparable magnitude of anti-collagen antibody responses, indicating the localization of the genetic defect at cellular levels other than B cells themselves. In contrast to immunization with native collagen, sensitization of DBA/1 mice with heat-denatured collagen failed to stimulate B cells, but resulted in selective generation of L3T4+ T cell-mediated immunity. These included anti-collagen delayed-type-hypersensitivity (DTH) responses and the generation of various interleukins (IL) responsible for antibody production as well as DTH responses. It was demonstrated that there was appreciable difference in the magnitudes of these responses between lymphoid cells from high and low responder mice. Differential effects of sensitization with heat-denatured collagen in high versus low responders were reflected on the genetic difference in the development of chronic arthritis. A typical arthritis was induced neither in denatured collagen-sensitized DBA/1 mice nor in unsensitized mice transferred with anti-collagen antiserum. However, the antiserum transfer into denatured collagen-sensitized DBA/1 mice induced chronic perpetuating arthritis. This sharply contrasted with the failure of the same aliquot of the antiserum to induce a chronic arthritis when inoculated into denatured collagen-sensitized low responder mice. These results indicate that the genetic control of the induction of arthritis is expressed on L3T4+ T cells which are required for generating anti-collagen humoral as well as cell-mediated immunities as assessed by DTH responses in vivo or lymphokine productions in vitro.
Regional immunology 2(4):203-12.
