Androgen Receptors in Human Synoviocytes and Androgen Regulation of Interleukin 1ß (IL-1ß) Induced IL-6 Production: A Link Between Hypoandrogenicity and Rheumatoid Arthritis?

ZHILA KHALKHALI-ELLIS, ROBERT J. HANDA, RICHARD H. PRICE Jr, BRIAN D. ADAMS, JOHN J. CALLAGHAN, and MARY J.C. HENDRIX

ABSTRACT.

Objective. To investigate the hypothesis that synoviocytes possess androgen receptors (AR) that could be modulated by the non-aromatizable androgen, dihydrotestosterone (DHT), resulting in altered levels of inflammatory cytokines.

Methods. Using molecular analyses of AR in combination with the multiprobe ribonuclease protection assay and ELISA, we investigated the presence of AR and the effect of DHT on interleukin 1ß (IL-1ß) induced expression of the IL-6 superfamily of cytokines in synoviocytes.

Results. Our studies corroborate the presence of AR in synoviocytes. DHT exerts a suppressive effect on IL-1ß induced IL-6, macrophage-colony stimulating factor (CSF), and granulocyte-CSF production by synoviocytes. This modulatory effect is exerted at both the transcriptional and translational level; 17ß-estradiol, at high concentrations, had a stimulatory effect.

Conclusion. The identification of functional AR in synoviocytes and the modulatory effect of DHT on the inflammatory process in the joint suggest a direct link between hypoandrogenicity and rheumatoid arthritis (RA) disease status. Understanding the complex regulation of inflammatory cytokines by hormones may contribute to the development of new therapeutic targets for clinical intervention in RA. (J Rheumatol 2002;29:1843-6)

Key Indexing Terms:

ANDROGEN
ANDROGEN RECEPTOR
SYNOVIOCYTES
RHEUMATOID ARTHRITIS
INTERLEUKIN 6

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From the Departments of Anatomy and Cell Biology and Orthopaedic Surgery, University of Iowa, Iowa City, Iowa; and the Department of Anatomy and Neurobiology, Colorado State University, Ft. Collins, Colorado, USA.

Supported in part by Howard Hughes Investigator Award and College of Medicine Award to Dr. Khalkhali-Ellis.

Z. Khalkhali-Ellis, PhD, Department of Anatomy and Cell Biology; R.J. Handa, PhD; R.H. Price Jr, PhD, Department of Anatomy and Neurobiology; B.D. Adams, MD; J.J. Callaghan, MD, Department of Orthopaedic Surgery; M.J.C. Hendrix, PhD, Department of Anatomy and Cell Biology.

Address reprint requests to Dr. Z. Khalkhali-Ellis, Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA. E-mail: zhila-ellis@uiowa.edu

Submitted September 24, 2001; revision accepted March 23, 2002.

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