CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis.

The mechanism responsible for trafficking of monocyte-derived macrophages into kidney in the puromycin aminonucleoside model of nephrotic syndrome in rats (PAN-NS), and the significance of this infiltration, remain largely unknown. CXCL10, a chemokine secreted in many T helper type 1 (Th1) inflammatory diseases, exhibits important roles in trafficking of monocytes and activated T cells. We hypothesized that induction of circulating interferon (IFN)-γ and glomerular tumour necrosis factor (TNF)-α during PAN-NS would stimulate the release of CXCL10 by podocytes, leading to infiltration of activated immune cells and greater glomerular injury. We found that serum IFN-γ, glomerular Cxcl10 mRNA and intra- and peri-glomerular macrophage infiltration were induced strongly during the late acute phase of PAN-NS in Wistar rats, but not in nude (Foxn1(rnu/rnu) ) rats lacking functional effector T lymphocytes. Wistar rats also developed significantly greater proteinuria than nude rats, which could be abolished by macrophage depletion. Stimulation of cultured podocytes with both IFN-γ and TNF-α markedly induced the expression of Cxcl10 mRNA and CXCL10 secretion. Together, these data support our hypothesis that increased circulating IFN-γ and glomerular TNF-α induce synergistically the production and secretion of CXCL10 by podocytes, attracting activated macrophages into kidney tissue. The study also suggests that IFN-γ, secreted from Th1 lymphocytes, may prime proinflammatory macrophages that consequently aggravate renal injury.

Suppression of adjuvant arthritis by kappa-opioid receptor agonist: effect of route of administration and strain differences.

It is well established that kappa-opioid receptor agonists exert antiinflammatory and antihyperalgesic effects during nonspecific inflammation as well as suppressive effects on the development of humoral and cell-mediated immune responses to foreign antigens. The aim of this study was to investigate the ability of the kappa-opioid receptor agonist MR 2034 to modulate adjuvant arthritis in the rat. In the first series of experiments, treatments of Wistar rats were performed using several routes of drug administration: intraperitoneal (ip), intracaudal (ic), intracerebroventricular (icv) and intraplantar (ipl). MR 2034 significantly suppressed joint swelling after ip and ic treatment, slightly reduced inflammation after ipl treatment, and did not produce any effect after icv treatment. In the second series of experiments, the suppressive effect of ip injected MR 2034 was investigated using Wistar, Dark August (DA) and Lewis rats. In Wistar rats, MR 2034 significantly decreased the incidence of adjuvant arthritis, and suppressed mean joint score and aggregate joint score. Similarly, in DA rats treated with MR 2034, mean arthritic score was significantly suppressed, but other clinical parameters were not affected. In Lewis rats, however, ip treatment with MR 2034 failed to produce any suppressive effect on joint disease and even potentiated the initial development of arthritis. These data suggest that immunosuppressive and antiinflammatory action of MR 2034 markedly depend on the route of drug administration and strain susceptibility to opioids.

Opioid receptor-mediated suppression of humoral immune response in vivo and in vitro: involvement of kappa opioid receptors.

The selective kappa opioid receptor agonist MR 2034 exerted pronounced suppression of plaque-forming cell (PFC) response following intraperitoneal (i.p.) administration in the rat. Pretreatment with preferential kappa and mu opioid receptor antagonists MR 2266 and naloxone, respectively, revealed that this effect was mediated mainly by kappa, and to a low extent by mu opioid receptors. Intracerebroventricular (i.c.v.) administration of quaternary naltrexone (QNtx) moderately attenuated, whereas i.p. given QNtx completely prevented the suppressive effect of MR 2034, suggesting a peripheral mechanism of action, and only minor involvement of brain opioid receptors. MR 2034 markedly decreased the PFC response of spleen cells obtained from in vivo immunized rats, treated in vitro with the opiate. The immunosuppressive action of MR 2034 in vitro was completely and partially blocked by equimolar concentrations of MR 2266 and naloxone, respectively. Antagonists alone produced stimulation of PFC following i.p. administration in the rat, but did not affect PFC response upon in vitro treatment. These results suggest that peripheral kappa opioid receptors down-regulate primary humoral immune response in the rat, and that this effect may be produced by direct interference with plasma cell activity.

kappa-Opioid receptor functions: possible relevance to experimental allergic encephalomyelitis.

The present study deals with the influence of preferential kappa-opioid agonist MR 2034 on experimental allergic encephalomyelitis (EAE). For this purpose, 9-week-old male Dark August rats were treated intraperitoneally with 0.2 mg/kg of MR 2034 as follows: (a) from the day of EAE induction until sacrifice; (b) from the day of EAE induction until the appearance of neurological signs, and (c) from the appearance of neurological signs until sacrifice. Repeated injections of MR 2034 given during the whole period of observation produced the most pronounced suppression of EAE clinical signs, histological lesions in the brain and spinal cord, and anti-myelin basic protein antibody production. These results suggest that kappa-opioid receptors may be involved in the development of EAE.