Decreased 4-1BB expression on CD4+CD25 high regulatory T cells in peripheral blood of patients with multiple sclerosis.

As a tumour necrosis factor receptor superfamily member, 4-1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25(high) T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25(high) Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4-1BB and soluble 4-1BB (s4-1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4-1BB expression in their CD4+C25(high) Tregs and increased plasma s4-1BB protein levels. Moreover, the plasma s4-1BB levels of MS patients were shown to be inversely correlated with the 4-1BB surface expression of CD4+CD25(high) Tregs. The down-regulated 4-1BB expression on CD4+CD25(high) Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity.

Enhanced plasma levels of LIGHT in patients with acute atherothrombotic stroke.

OBJECTIVES: As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) was recently found to be associated with platelets and released upon activation. Increased plasma levels of LIGHT have been reported in patients with myocardial infarction and unstable angina. The aim of the study was to analyze plasma levels of LIGHT in acute ischemic atherosclerotic stroke. MATERIALS AND METHODS: The soluble LIGHT protein was analyzed by an enzyme-linked immunosorbent assay in peripheral blood of patients with acute ischemic atherosclerotic stroke (n = 20), asymptomatic carotid stenosis (n = 19) and normal controls (n = 23). RESULTS: During the initial 24 h after onset, the stroke patients had an increased plasma LIGHT levels as compared with normal controls. Moreover, the plasma LIGHT levels of the stroke patients were correlated with blood platelet count (r = 0.6341, P = 0.0027). CONCLUSION: The elevated LIGHT levels may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. We speculate that this derangement of LIGHT may be important for atherogenetic process of ischemic stroke.

Inhibition by nociceptin on excitatory non-adrenergic non-cholinergic response in guinea pig airways.

AIM: To study the effect of nociceptin (NC), a newly discovered heptadecapeptide, and U-50488H, a kappa-opioid receptor agonist, on excitatory non-adrenergic non-cholinergic (eNANC) constriction responses in guinea pig isolated bronchus. METHODS: An eNANC response was induced by electric field stimulation (EFS) in the preparation via activation of the sensory nerve terminals. The effect of NC and U-50488H was analyzed on the response. RESULTS: Nociceptin 0.001 - 0.1 micromol/L inhibited the eNANC constriction which was induced by EFS but not by capsaicin in guinea pig bronchus. The constriction inhibited by NC 0.01 micromol/L was (43 +/- 31) % compared with the control. After pretreatment with naloxone 0.1 micromol/L, the constriction was inhibited by (46 +/- 28) %, without marked change compared with the above figure. IC50 (95 % of confidence limits) was 6.12 (3.8 - 9.9) nmol/L. U-50488H also inhibited the EFS-evoked eNANC constriction and the effect was abolished after pretreatment with naloxone. IC50 (95 % of confidence limits) was 1.08 (0.5 - 2.2) micromol/L. Capsaicin 0.01 - 1 micromol/L caused a cumulative constriction response in the preparation. Moreover, the effect of capsaicin was not affected by pretreatment with NC 0.01 micromol/L or U-50488H 0.1 micromol/L. The constriction induced by exogenous neurokinin A, were also unaffected by treatment with NC 0.01 micromol/L or U-50488H 0.1 micromol/L in isolated bronchus. CONCLUSION: Nociceptin inhibits EFS-induced eNANC constriction, which is not reversed by naloxone, while U-50488H inhibits EFS-induced eNANC response via activation of opioid receptor in guinea pig airways.

Nociceptin inhibits electric field stimulation-induced cholinergic constrictions in rat airways.

AIM: To study the effect of nociceptin (orphanin FQ), a newly discovered heptadecapeptide, on cholinergic constrictions in isolated trachea and bronchus of rat. METHODS: The electric field stimulation (EFS) induced a monophasic constriction, which was due to an activation of the cholinergic nerves. RESULTS: Nociceptin 0.001-0.1 mumol/L inhibited cholinergic constriction in a concentration-dependent manner. IC50 (95% of confidence limits) were 0.06 (0.04-0.08) mumol/L and 0.07 (0.05-0.1) mumol/L in tracheae and bronchi respectively. The constrictions inhibited by nociceptin 0.01 mumol/L in traheae and bronchi were (58 +/- 32)% and (60 +/- 26)% respectively compared with the control, in which nociceptin was not applied. After pretreatment with naloxone 0.1 mumol/L, the constrictions were (60 +/- 19)% and (54 +/- 20)% (P > 0.05 vs the above figures). However, the constrictions induced by exogenous acetylcholine were unaffected by nociceptin 0.01 mumol/L. kappa-Opioid receptor agonist, U-50488H (0.01-1 mumol/L) did not affect the EFS-induced cholinergic constrictions in rat airways. CONCLUSION: Nociceptin inhibits EFS-induced cholinergic constriction, which is not affected by naloxone in rat airways.

Inhibitory effect of tetrandrine on C fiber activation-induced contractions in trachea and bronchus of guinea pig.

AIM: To study the inhibitory effects of tetrandrine (Tet) on an activation of the sensory nervous C fibers in isolated trachea and bronchus of guinea pig. METHOD: The electric field stimulation induced a phase II contraction of the preparations, which was due to an activation of the C fifers. The effects of Tet on phase II contraction were analyzed. RESULTS: Tet 0.3-30 mumol.L(-1) inhibited phase II contractions in a concentration-dependent manner. That phase II contractions inhibited by Tet 1 mumol.L(-1) were 40 +/- 38% and 75 +/- 22% of control in tracheae and bronchi respectively. After pretreatment with chlorphenamine or atropine phase II contraction were still reduced by Tet 1 mumol.L(-1), inhibitory rates being 70 +/- 16% and 64 +/- 16% of control, respectively. The contractile responses of the preparations to exogenous substance P, however, were unaffected by treatment with Tet 1 mumol.L(-1). CONCLUSION: Tet 1 mumol.L(-1) inhibits phase II contraction, related to the inhibition of local release of neuropeptides from C fibers of guinea pig airway.

Mediator difference in contractions between trachea and bronchus of guinea pig induced by stimulation of C-fibers in vitro.

In trachea and bronchus of guinea pig in vitro, electric field stimulation (EFS) induced a rapid contraction (phase I) followed by a long-lasting contraction (phase II). The pretreatments of chlorphenamine (Chl) 1 mumol.L-1 and disodium cromoglycate (Cro) 10 mumol.L-1 reduced the tracheal contraction of phase II from 49 +/- 23 mg and 34 +/- 18 mg to 27 +/- 21 and 18 +/- 12 mg, respectively. The contractile responses of the tracheae to increasing concentrations of substance P (SP) 0.1-3.0 mumol.L-1 were reduced by the pretreatment of Cro 10 mumol.L-1 (P < 0.01). On the contrary, the contractile responses of the bronchi were not inhibited by Cro or Chl but were inhibited by pretreatment of atropine 1 mumol.L-1 from 61 +/- 36 mg to 36 +/- 15 mg. These results show that there are different mechanisms in the EFS-induced contractions between the trachea and bronchus; that different mediators amplify the phase II contractions.

Effect of a single breath of cigarette smoke on slowly adapting receptors in canine lungs.

Inhalation of cigarette smoke has been shown to induce bronchoconstriction which should stimulate slowly adapting pulmonary stretch receptors (PSRs). To test this possibility, the activity of PSRs was recorded from fine afferent filaments of the vagus nerve before and after 120 ml of smoke generated from high-nicotine cigarettes was delivered into the lungs in a single breath in anesthetized, open-chest and artificially ventilated dogs. The base-line activity of PSRs did not change during the first two breaths following smoke delivery. However, PSR activity started to increase by the third breath (post-smoke), concomitant with an increase in tracheal (transpulmonary) pressure. Both the smoke-induced increase in tracheal pressure and the delayed effect on PSRs were prevented by a pretreatment with aerosolized isoproterenol, a bronchodilator, suggesting that the delayed response of PSRs to smoke was elicited by the change in bronchomotor tone. Although smoke evoked a delayed stimulation in the majority (61%) of the PSRs studied, it caused a mild delayed inhibition (24%) or had no effect (15%) in some of the receptors. The variable responses to smoke among PSRs are probably related to the smoke-induced heterogeneous changes of mechanical properties in the lungs and their different anatomic locations.

Antiviral immune responses of fully allogeneic irradiation bone marrow mouse chimeras.

In (B10.BR----B10) chimeras infected with lymphocytic choriomeningitis (LCM) virus higher titers were attained in spleens and livers than in organs of the mice used for their construction, and the subsequent elimination was retarded, but eventually the virus was cleared. The numbers of LCM virus-specific CTL and their precursors as quantitated with chromium-release assay and limiting dilution method, respectively, were lower in chimeras than in B10.BR or C57BL/10J mice, and fewer were restricted for the haplotypes of the donors than of the recipients. The same was true with regard to antiviral effector cells, which were determined by adoptive immunization. The numbers of spleen cells releasing IgM and IgG antiviral antibodies were virtually as high in chimeras as they were in C57BL/10J and B10.BR mice. Transfer of immune splenocytes from either B10.BR or C57BL/10J mice resulted in incomplete virus elimination from the spleens of infected chimeras, whereas injection of a mixture of the two types of immune cells led to efficient clearance. We conclude that in the chimeras cells of both donor and recipient haplotypes participate in the infection, which is terminated by H-2k- and H-2b-restricted T lymphocytes that these animals are capable of generating. We conclude, furthermore, that clearance of the LCM virus from the tissues requires contact between effector and target cells.

Bronchoconstriction and delayed rapid shallow breathing induced by cigarette smoke inhalation in anesthetized rats.

Bronchomotor and ventilatory responses to inhalation of cigarette smoke (50% concentration, 6 ml) were studied in anesthetized and vagotomized Sprague-Dawley rats. Low-nicotine cigarette smoke did not cause any detectable delayed response, whereas high-nicotine cigarette smoke induced rapid, shallow breathing, and a marked increase in airway resistance (RL). The increase in f reached a peak (delta f = 43 +/- 8%) at the 5th breath after the onset of smoke inhalation, preceding both the decrease in VT (delta VT = -27 +/- 4%) and the increase in RL (delta RL = 89 +/- 19%); the latter 2 reached their peaks at approximately the 10th breath, displaying a similar temporal pattern of responses between them. The bronchomotor response to high-nicotine cigarette smoke was slightly attenuated but not prevented by prior administration of isoproterenol (0.2 mg/kg, intravenously [iv]), nor was the smoke-induced rapid, shallow breathing. In contrast, prior administration of mecamylamine (0.9 mg/kg, iv) completely abolished both the bronchomotor and ventilatory responses to smoke inhalation, indicating that nicotine is the primary causative agent responsible for these changes.