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

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Abstract
Objective Macrophages release cytokines, such as tumor necrosis factor α (TNFα), 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. Fcγ 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 (17β-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 17β-estradiol, physiologic levels (1 × 10−8M) of 17β-estradiol, or 1 × 10−8M 17β-estradiol followed by withdrawal of 17β-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 17β-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 17β-estradiol, and the observed increase in message was dependent on transcription. CD16 receptor levels on CD14+, transforming growth factor β–treated primary monocytes also increased in cells deprived of 17β-estradiol. Analysis of the cytokines released showed that CD16 crosslinking stimulated significant increases in TNFα, IL-1β, 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.