Abstract
Deposition of amyloid-beta (Aβ) peptides has been shown to induce the release of inflammatory factors by activated microglia and brain infiltrating monocytes/macrophages. Interestingly, the enzyme transglutaminase 2 (TG2) has been shown to play a key role in neuroinflammation and regulation of transcription factors involved in immunomodulation. In this study, we aimed to better elucidate the mechanisms underlying TG2 involvement in the pro-inflammatory signaling pathway activated by fibrillar Aβ1–42 in THP-1 monocytes. Cell exposure for 24 h to 500 nM Aβ1–42, induced the up-regulation of CD14, CD16, and TG2, suggesting THP-1 cell functional activation. Aβ1–42 also increased the production of reactive oxygen species, that was reduced by the pre-incubation with genistein (25 µg/ml), a soy isoflavone with antioxidant properties. Moreover, IL-1β and IL-6 mRNA transcript and protein levels were eightfold increased in Aβ1–42-treated THP-1 monocytes. Interestingly, these effects were significantly reduced by R283 (~45%), a specific inhibitor of TG activity, and genistein (~40%). Aβ1–42 induced the activation of p54/p46 JNK, as well as ERK 1/2 at a lower extent. The inactivation of ERK1/2 signalling pathway, but not JNK, by either genistein or U0126, a MEK1/2 inhibitor, was not able to blunt Aβ1–42-induced TG2 up-regulation, that, instead, was significantly reduced by R283. Aβ1–42 also induced AP-1 activation that was not significantly affected by genistein or U0126, while was strongly reduced by R283. Our preliminary findings first suggest that TG2 up-regulation is involved in the pro-inflammatory activation of THP-1 monocytes induced by Aβ1–42 via AP1/JNK signalling pathways.
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Currò, M., Gangemi, C., Giunta, M.L. et al. Transglutaminase 2 is involved in amyloid-beta1–42-induced pro-inflammatory activation via AP1/JNK signalling pathways in THP-1 monocytes. Amino Acids 49, 659–669 (2017). https://doi.org/10.1007/s00726-016-2366-1
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DOI: https://doi.org/10.1007/s00726-016-2366-1