Molecular Neurobiology

, Volume 49, Issue 3, pp 1487–1500 | Cite as

Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia

  • Hongquan Dong
  • Wei Zhang
  • Xiaoning Zeng
  • Gang Hu
  • Huiwen Zhang
  • Shaoheng HeEmail author
  • Shu ZhangEmail author


Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.


Histamine Microglia activation Histamine receptors Inflammatory factors Neuroinflammation 



This project was sponsored by the grants from the National Natural Science Foundation of China (no. 81102422, 81373398), the Natural Science Foundation of Jiangsu Province (BK2010020), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Conflict of Interest

The authors declare that this article content has no conflicts of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Clinical Research CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of AnesthesiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  3. 3.Department of Pharmacology, Jiangsu Key Laboratory of NeurodegenerationNanjing Medical UniversityNanjingPeople’s Republic of China

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