beta-adrenergic receptor stimulation selectively inhibits IL-12p40 releasein microglia

The cytokine interleukin-12 (IL-12) is mainly produced in response to bacte rial or parasitic infections. We examined the capacity of mouse brain micro glia to release IL-12 forms upon challenge with bacterial lipopolysaccharid e (LPS) and studied its modulation by sympathomimetics. LPS evoked the rele ase of IL-12p40 whereas the heterodimeric form, IL-12p70 was virtually unde tectable. Sympathomimetics such as salbutamol dose-dependently inhibited IL -12p40 release, whereas the production of IL-6, TNF alpha and MIP-1 alpha w as only marginally influenced. The inhibitory effect of salbutamol could be abolished by beta -antagonists, such as oxprenolol. The cAMP-elevating age nt forskolin could mimic the effects of beta -agonists, indicating that IL- 12p40 release inhibition involves intracellular cAMP accumulation. While mi croglial IL-12p40 may play a role in the regulation of IL-12p70 bioactivity , microglial release is itself modulated by IL-12p70. Recombinant IL-12p70 was found to enhance the LPS-evoked release of MIP-1 alpha and to have a bi phasic effect on both TNF alpha and MIP-1 alpha with release augmentation a t lower and attenuation at higher doses. Finally, no functional correlation was found between the release of IL-12p40 and the induction of Kv 1.3 pota ssium channels, another marker of microglial activation. Taken together, be ta (2)-adrenoreceptor-mediated effects on microglial cyto- and chemokine re lease via cAMP accumulation could modulate inflammatory cascades during bac terial infections. (C) 2001 Elsevier Science B.V. All rights reserved.