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Published online before print October 5, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406237

Received for publication April 3, 2006.
Revised August 23, 2006.
Accepted for publication September 11, 2006.

Article

Differential involvement of RelB in morphine-induced modulation of chemotaxis, NO, and cytokine production in murine macrophages and lymphocytes

Department of Pharmacology, University of Milan, Milan, Italy

^@ To whom correspondence should be addressed. E-mail: paola.sacerdote{at}unimi.it.

	Abstract

Acute morphine impairs innate and acquired immunity. The mechanisms involved in immunosuppression have not been well defined yet. The transcription factor NF-B is a central regulator of immunity, and of the NF-B family, RelB is particularly involved in the expression of genes important in immune responses. We investigated the involvement of RelB in morphine-induced immunosuppression in mice deficient for the RelB factor. RelB-/- mice and wild-type (WT) controls were injected s.c. with morphine 20 mg/Kg, and 1 h later, immune parameters were evaluated. Morphine significantly reduced macrophage production of the proinflammatory cytokines IL-1, TNF-, and IL-12 in WT animals, and the drug failed to diminish the production of these cytokines in the RelB-/- mice. In contrast, the anti-inflammatory cytokine IL-10 was similarly affected in the two strains. Macrophage NO production was modulated by morphine in WT animals only, and morphine similarly decreased macrophage chemotaxis in the presence or in the absence of RelB. When Th1 and Th2 cytokines were evaluated, we observed a clear morphine-induced reduction of IL-2 and IFN- production by WT splenocytes, whereas no effect of the drug was observed in RelB-/- mice. On the contrary, the production of the Th2 cytokines IL-4 and IL-10 was lessened to the same degree by morphine in WT and RelB-/- mice. In conclusion, our data suggest that RelB is an important target for morphine modulation of proinflammatory and Th1 cytokines. They also indicate that morphine uses multiple intracellular pathways to exert its generalized immunosuppression.

Key Words: monocytes • opioid receptors • Th1/Th2 • transcription factors

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