A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse

Androstene hormones as regulators of regulatory T cells

Dominick L. Auci, L. Kaler, Sandhya Subramanian, Yugin Huang, J. Frincke, C. Reading, Halina Offner

Research output: Chapter in Book/Report/Conference proceedingConference contribution

29 Citations (Scopus)

Abstract

Dehydroepiandrosterone (DHEA) has attracted much interest because of its many antiaging, metabolic and immune-modulating effects in rodents. Synthetic derivatives, such as 5-androstene-16α-fluoro-17-one (HE2500) and certain natural metabolites also provide benefit in various animal models of autoimmune and metabolic diseases. But, like DHEA, low potency and low oral bioavailability suggested limited usefulness of these compounds in humans. We hypothesized that HE3286, a novel 17-ethynyl derivative would be orally bioavailable, more potent, and chemically more useful in man than its parent compound. We found that on a dose/mass basis, HE3286 demonstrated up to 25% oral bioavailability in mice. In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-α, IL-6, and IL-17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. HE3286 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction. Instead, benefit was associated with increases in numbers and function of CD4+CD25+FOXp3+CD127- regulatory T cells (Treg). To our knowledge, this is probably the first study to report that an orally bioavailable synthetic analogue of DHEA can ameliorate ongoing disease in a CIA mouse model with relevance to rheumatoid arthritis (RA) and to correlate that finding with decreases in proinflammatory cytokines and increases in T reg cells. Hormones targeting Treg cells hold the intriguing potential to treat autoimmune, infectious, and neoplastic diseases.

Original languageEnglish (US)
Title of host publicationAnnals of the New York Academy of Sciences
Pages630-640
Number of pages11
Volume1110
DOIs
StatePublished - Sep 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1110
ISSN (Print)00778923
ISSN (Electronic)17496632

Fingerprint

Androstenes
Experimental Arthritis
T-cells
Regulatory T-Lymphocytes
Dehydroepiandrosterone
Collagen
Hormones
Biological Availability
Animals
Derivatives
Inbred DBA Mouse
Mixed Lymphocyte Culture Test
Lymphocytes
Interleukin-17
Metabolic Diseases
Delayed Hypersensitivity
Metabolites
Mitogens
Autoimmune Diseases
Arthritis

Keywords

  • Androstene
  • Arthritis
  • Cytokines
  • DHEA metabolites
  • Regulatory T cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Auci, D. L., Kaler, L., Subramanian, S., Huang, Y., Frincke, J., Reading, C., & Offner, H. (2007). A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells. In Annals of the New York Academy of Sciences (Vol. 1110, pp. 630-640). (Annals of the New York Academy of Sciences; Vol. 1110). https://doi.org/10.1196/annals.1423.066

A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse : Androstene hormones as regulators of regulatory T cells. / Auci, Dominick L.; Kaler, L.; Subramanian, Sandhya; Huang, Yugin; Frincke, J.; Reading, C.; Offner, Halina.

Annals of the New York Academy of Sciences. Vol. 1110 2007. p. 630-640 (Annals of the New York Academy of Sciences; Vol. 1110).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Auci, DL, Kaler, L, Subramanian, S, Huang, Y, Frincke, J, Reading, C & Offner, H 2007, A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells. in Annals of the New York Academy of Sciences. vol. 1110, Annals of the New York Academy of Sciences, vol. 1110, pp. 630-640. https://doi.org/10.1196/annals.1423.066
Auci DL, Kaler L, Subramanian S, Huang Y, Frincke J, Reading C et al. A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells. In Annals of the New York Academy of Sciences. Vol. 1110. 2007. p. 630-640. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1423.066
Auci, Dominick L. ; Kaler, L. ; Subramanian, Sandhya ; Huang, Yugin ; Frincke, J. ; Reading, C. ; Offner, Halina. / A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse : Androstene hormones as regulators of regulatory T cells. Annals of the New York Academy of Sciences. Vol. 1110 2007. pp. 630-640 (Annals of the New York Academy of Sciences).
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