Methamphetamine (METH) elicits neuroinflammatory effects that may implicate its regulatory role on the microglial immune response. However, the mechanism underlying this remains unclear. In the present study, the effects of METH on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) productions were tested in BV-2 cells and primary microglial cells. Additionally, western blot analysis was used to examine the phosphorylation of mitogenactivated protein kinases (MAPKs). Next, we detected the alterations in cAMP content and the phosphorylation levels of CREB in microglial cells to determine the involvement of the cAMP/CREB signaling pathway. We also used an adenylyl cyclase (AC) agonist (forskolin) and antagonist (MDL-12330A) and a PKA antagonist (H89) to confirm their participation. We observed that METH alone did not affect the production of IL-6 or TNF-α. In contrast, METH augmented the IL-6 production and inhibited the TNF-α production induced by LPS. A similar effect of forskolin was also observed in BV-2 cells. While MAPK activation was not influenced by METH alone, the LPS-induced phosphorylation of p38, JNK and ERK1/2 were all reduced by METH. Both the concentration of cAMP and the phosphorylation of CREB were increased by METH in LPS-activated microglial cells. The effects of METH were altered by MDL-12330A and H89. Moreover, the inhibition of the phosphorylation of ERK1/2 by METH was also reversed. These results suggest that the differential regulation of IL-6 and TNF-α by METH in LPS-activated microglial cells may be attributable to the cAMP/PKA/CREB signaling pathway.
Keywords: IL-6; Methamphetamine; Microglial cells; TNF-α; cAMP.
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