HIV-1 Envelope Glycoproteins Induce the Production of TNF-α and IL-10 in Human Monocytes by Activating Calcium Pathway

Sci Rep. 2018 Nov 21;8(1):17215. doi: 10.1038/s41598-018-35478-1.


Human HIV-1 infection leads inevitably to a chronic hyper-immune-activation. However, the nature of the targeted receptors and the pathways involved remain to be fully elucidated. We demonstrate that X4-tropic gp120 induced the production of TNF-α and IL-10 by monocytes through activation of a cell membrane receptor, distinct from the CD4, CXCR4, and MR receptors. Gp120 failed to stimulate IL-10 and TNF-α production by monocytes in Ca2+ free medium. This failure was total for IL-10 and partial for TNF-α. However, IL-10 and TNF-α production was fully restored following the addition of exogenous calcium. Accordingly, addition of BAPTA-AM and cyclosporine-A, fully and partially inhibited IL-10 and TNF-α respectively. The PKA pathway was crucial for IL-10 production but only partially involved in gp120-induced TNF-α. The PLC pathway was partially and equivalently involved in gp120-induced TNF-α and IL-10. Moreover, the inhibition of PI3K, ERK1/2, p38 MAP-kinases and NF-κB pathways totally abolished the production of both cytokines. In conclusion, this study revealed the crucial calcium signaling pathway triggered by HIV-1 gp120 to control the production of these two cytokines: TNF-α and IL-10. The finding could help in the development of a new therapeutic strategy to alleviate the chronic hyper-immune-activation observed in HIV-1 infected patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • HIV Envelope Protein gp120 / metabolism*
  • Humans
  • Interleukin-10 / metabolism*
  • Monocytes / drug effects*
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Type C Phospholipases / metabolism


  • HIV Envelope Protein gp120
  • IL10 protein, human
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • gp120 protein, Human immunodeficiency virus 1
  • Interleukin-10
  • Cyclic AMP-Dependent Protein Kinases
  • Type C Phospholipases
  • Calcium