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


CONCLUSIONS
Estrogen can modulate proinflammatory cytokine release from activated monocytes and/or macrophages, in part through modulation of CD16 expression.
Kramer
P R
PR
Department of Biomedical Sciences, Baylor College of Medicine, Texas A&M University Health Science Center, Dallas, 75246, USA. pkramer@tambcd.edu
Kramer
S F
SF
Guan
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G
D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D017455:Receptors, IgE; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol