17 beta-estradiol regulates cytokine release through modulation of CD16 expression in monocytes and monocyte-derived macrophages

Arthritis Rheum. 2004 Jun;50(6):1967-75. doi: 10.1002/art.20309.


Objective: Macrophages release cytokines, such as tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and IL-6, which modulate the symptoms of rheumatoid arthritis (RA). Macrophage release of these cytokines can be modulated by estrogen. Fc gamma receptor type IIIA (CD16a) is a receptor expressed on macrophages that selectively binds IgG molecules, an important rheumatoid factor in RA. Binding of CD16 by anti-CD16 monoclonal antibodies stimulates macrophage cytokine release. We undertook this study to test the hypothesis that decreased concentrations of estrogen (17 beta-estradiol) directly cause an increase in CD16 expression, resulting in increased release of proinflammatory cytokines from monocytes and/or macrophages upon receptor binding.

Methods: THP-1 cells and female human primary monocytes and monocyte-derived macrophages were treated with no 17 beta-estradiol, physiologic levels (1 x 10(-8)M) of 17 beta-estradiol, or 1 x 10(-8)M 17 beta-estradiol followed by withdrawal of 17 beta-estradiol. Surface expression of CD16 and CD16 messenger RNA was measured using fluorescence-activated cell sorting (FACS) and semiquantitative reverse transcription-polymerase chain reaction, respectively. Cytokine release from 17 beta-estradiol-treated or untreated monocytes was then quantitated by enzyme-linked immunosorbent assay and FACS after crosslinking the receptor with anti-CD16 antibodies.

Results: CD16 transcript significantly increased in macrophage-like THP-1 cells and in primary, peripheral blood macrophages in the absence of 17 beta-estradiol, and the observed increase in message was dependent on transcription. CD16 receptor levels on CD14+, transforming growth factor beta-treated primary monocytes also increased in cells deprived of 17 beta-estradiol. Analysis of the cytokines released showed that CD16 crosslinking stimulated significant increases in TNF alpha, IL-1 beta, and IL-6 due to the absence of estrogen.

Conclusion: Estrogen can modulate proinflammatory cytokine release from activated monocytes and/or macrophages, in part through modulation of CD16 expression.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cells, Cultured
  • Cytokines / metabolism*
  • Estradiol / pharmacology*
  • Extracellular Space / metabolism
  • Female
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Humans
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharide Receptors / genetics
  • Macrophages / drug effects*
  • Macrophages / physiology
  • Middle Aged
  • Monocytes / drug effects*
  • Monocytes / physiology
  • RNA, Messenger / metabolism
  • Receptors, IgE / genetics
  • Receptors, IgG / genetics*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Cytokines
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharide Receptors
  • RNA, Messenger
  • Receptors, IgE
  • Receptors, IgG
  • Tumor Necrosis Factor-alpha
  • Estradiol