Anti-inflammatory and immune regulatory properties of 5-androsten-3beta, 17beta-diol (HE2100), and synthetic analogue HE3204: implications for treatment of autoimmune diseases.
5-Androsten-3beta, 17beta-diol (HE2100), and a synthetic analogue HE3204 are regarded as immune-regulating hormones, because both induce changes in the reporter antigen-popliteal lymph node assay (RA-PLNA). Mice were injected in the footpad with either HE2100 or HE3204 (0.01-3 mg), and a nonsensitizing dose of trinitrophenyl ovalbumin (TNP-OVA) was used as bystander reporter antigen. Seven days later, nodes were removed and numbers of cells (CD3, CD4, CD8, CD19; flow cytometry), TNP-specific IgM, IgG1, and IgG2a antibody-forming cells (AFCs; ELISPOT assay), and cytokines (interleukin-4 [IL-4], interferon-gamma [IFN-gamma]; ELISA) were measured. HE2100 and HE3204 increased cell numbers in a dose-dependent fashion. T (helper and suppressor) cells and B cells were increased (>5-fold). HE3204 was apparently twice as potent as HE2100. Both increased the B/T ratio (fivefold), increased TNP-specific IgM and IgG1 ( approximately 50-fold), and induced IgG2a AFCs. Both increased IL-4 and IFN-gamma secretion (up to threefold). Both displayed anti-inflammatory activity in the murine model of carrageenan-induced pleurisy, as evidenced by reduced neutrophil numbers and exudate volumes. Our observations suggest that both HE2100 and HE3204 are immune-regulating steroid hormones that exhibit anti-inflammatory properties. HE2100 (1 mg/mouse per day) provided significant benefit when given at disease onset in the SJL/J female mouse model of experimental autoimmune encephalomyelitis. These compounds and their analogues are candidates for further testing in autoimmune diseases.
Auci
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D
Hollis-Eden Pharmaceuticals, 4435 Eastgate Mall, Suite 400, San Diego, CA 92121, USA. Dauci@holliseden.com
Nicoletti
F
F
Mangano
K
K
Pieters
R
R
Nierkens
S
S
Morgan
L
L
Offner
H
H
Frincke
J
J
Reading
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C
D000595:Amino Acid Sequence; D015114:Androstenediol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D000737:Androstenols / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010998:Pleurisy / Q000188:drug therapy; D012772:Shock, Septic / Q000188:drug therapy
D000737:Androstenols; D000893:Anti-Inflammatory Agents; C511216:HE3204; D015114:Androstenediol