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PubMed2005

Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats.

Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw(-1)) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg(-1)), or cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) [endothelin (ET)(A) receptor antagonist; 30 nmol paw(-1)] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw(-1)). However, dexamethasone (2 mg kg(-1)), morphine (3-12 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-alpha (50 microl paw(-1)) nor against IL-18 (10 microg paw(-1)) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw(-1)) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ET(B) receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.

Analgesics↗
PubMed1998

No evidence of IFN-gamma increase in the serum of HIV-positive and healthy subjects after subcutaneous injection of a non-fermented viscum album L. extract.

Iscador, an aqueous extract of Viscum album L., has been used for more than 80 years as an anticancer drug. Due to its immunomodulatory potential, since the onset of the AIDS epidemic it has also been applied in the treatment of HIV-positive and AIDS patients in the form of the preparation V. album QuFrF (VaQuFrF; Labor Hiscia, Arlesheim, Switzerland). In in vitro investigations, incubation of peripheral blood mononuclear cells with V. album L. extracts resulted in stimulation of lymphocyte activity with increased gene expression and release of various cytokines and also of interferon gamma (IFN-gamma). In the latent phase, HIV positives exhibit only slightly elevated IFN-gamma concentrations in serum in comparison with HIV negatives, but in the acute phase of AIDS, there is an increase in levels of IFN-gamma. As the assay of cytokine levels in serum is a simple method of measuring immune system reactions, the aim of this trial was to determine whether increases in serum IFN-gamma levels in HIV positives and HIV negatives can be detected using this method after repeated injections of VaQuFrF. Five healthy subjects and 13 HIV-positive patients were investigated. IFN-gamma concentrations in serum were assayed using an ELISA test kit (ELISA test; ENDOGEN, Cambridge, Mass., USA). No drug-related elevation of serum IFN-gamma was observed at any time point during the trial. It can thus be concluded that this method is not suitable for direct investigation of the immunomodulatory effects of VaQuFrF in vivo.

Adjuvants, Immunologic↗