Anandamide enhances IL‐10 production in activated microglia by targeting CB₂ receptors: Roles of ERK1/2, JNK, and NF‐κB

Abstract

The endocannabinoid system exhibits anti-inflammatory properties by regulating cytokine production. Anandamide (AEA) down-regulates proinflammatory cytokines in a viral model of multiple sclerosis (MS). However, little is known about the mechanisms by which AEA exerts these effects. Microglial cells are the main source of cytokines within the brain and the first barrier of defense against pathogens by acting as antigen presenting cells. IL-10 is a key physiological negative regulator of microglial activation. In this study we show that AEA enhances LPS/IFNgamma-induced IL-10 production in microglia by targeting CB(2) receptors through the activation of ERK1/2 and JNK MAPKs. AEA also inhibits NF-kappaB activation by interfering with the phosphorylation of IkappaBalpha, which may result in an increase of IL-10 production. Moreover, endogenously produced IL-10 negatively regulates IL-12 and IL-23 cytokines, which in its turn modify the pattern of expression of transcription factors involved in Th commitment of splenocytes. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases.

Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection

“…A third subgroup, M2b, includes regulatory macrophages activated by immune complexesϩToll-like receptors/IL-1R ligands (reviewed in 38 -41 ). Because the CB2R receptor regulates the balance of Th1-proinflammatory to Th2-anti-inflammatory cytokines, 11 as well as enhances the expression of IL-10 in vitro, 32,42 we decided to explore the effects of JWH-133 on anti-inflammatory and M2 markers. Interestingly, our data show that brain ischemia causes the expression of the M2-polarizing cytokines TGF-␤ and IL-10, which are in turn required for M2c activation, and also of Ym1, a secretory chitinase-like protein marker of the M2a state 38,41,43 ; this is consistent with the coexistence of different subsets of macrophage/microglial cells in the ipsilesional hemisphere and suggests an endogenous protective response.…”

Identification of prostamides, fatty acyl ethanolamines, and their biosynthetic precursors in rabbit cornea

“…the tissue specifi c distribution of sn -1 docosahexanoyl species of PC ( 43 ). Although A-EA is considered a minor lipid species, representing only 1-10% of total FA-EA in human membranes under basal conditions, studies carried out in brain and nervous tissue indicate A-EA levels are increased in response to injury ( 44,45 ), and that A-EA participates as an antiinfl ammatory agent of the immune response ( 25,46 ). Few studies have examined the actions of A-EA per se in the cornea; however, it is a highly innervated tissue, and CB 1 receptors expressed on corneal sensory nerves stimulated by an agonist were found to support a role in contributing to antinociception in the anterior eye ( 47 ).…”

Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells

“…Thus, the question is raised whether both classes of drugs inhibit NF-B. Inhibition of NF-B by cannabinoids has indeed been observed repeatedly (Nakajima et al, 2006;Correa et al, 2010). However, the precise mechanisms and the question about which receptors mediate such effects are not completely clear.…”