Abstract
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[DTrp-DAsp-Pro-DVal-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 μg paw-1), and N-cys-2,6 dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarboyl-d-norleucine (BQ788) (ETB receptor antagonist; 3-30 nmol paw-1) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-α (50 μl paw-1) nor against IL-18 (10 μg 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 ETB receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.
Footnotes
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This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Pesquisa, Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, and Programa de Núcleos de Exceleência, Brazil; and National Institute of Biological Standards and Control, South Mimms, Hertfordshire, UK. Part of this work has been presented as an abstract at the XXXIV Brazilian Congress of Pharmacology and Experimental Therapeutics, October 28-31, 2002, Águas de Lindoia, São Paulo, Brazil.
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W.A.V. and R.O.M. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.089409.
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ABBREVIATIONS: IL, interleukin; Th1, T helper 1; rhIL-12, recombinant human interleukin 12; TNF, tumor necrosis factor; ET, endothelin; i.pl., intraplantar; MK886, 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid (sodium); LPS, lipopolysaccharide; BQ123, cyclo[DTrp-DAsp-Pro-DVal-Leu]; BQ788, N-cys-2,6 dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarboyl-d-norleucine; ANOVA, analysis of variance.
- Received May 11, 2005.
- Accepted July 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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