Immune enhancing effects of dehydroepiandrosterone and dehydroepiandrosterone sulphate and the role of steroid sulphatase.
Steroid hormones, such as glucocorticoids (GC), influence immune and inflammatory responses through their suppressive actions. Recent evidence suggests that another steroid hormone, dehydroepiandrosterone (DHEA), provides an immunostimulatory influence opposing the effect of GC. DHEA circulates in its inactive sulphated form, DHEAS, requiring conversion to DHEA by a steroid sulphatase (SS) enzyme for biological activity. Therefore, inhibition of SS activity may affect immune responses, allowing endogenous GC effects to predominate. We have shown that administration of DHEA and DHEAS in contact sensitization (CS) augments ear swelling by 39 and 46% respectively (P < 0.001). DHEAS at doses of 0.5, 5 and 50 mg/kg reverses the inhibitory effect of corticosterone (5 mg/kg) (P < 0.01). In CS, CT2251 (SS inhibitor) at 10 and 0.1 mg/kg inhibited ear swelling by 61 and 38% (P < 0.05) respectively. In addition, it inhibited DHEAS-augmented responses by 49 and 35% respectively (P < 0.05), with no effect on DHEA-augmented responses. DHEAS reversed CT2251 inhibition of the CS response with complete reversal at 50 mg/kg (P < 0.05). DHEAS and CT2251 appear to affect cellular infiltration into the ear, since DHEAS increased the number of lymphocytes by 63.8% and macrophages by 107% (P < 0.001), whereas CT2251 at 0.1 mg/kg decreased the number of lymphocytes by 65% (P < 0.001) and macrophages by 80% (P < 0.001). DHEAS, CT2251 and dexamethasone had no effect on oedema in the ear. From our data we have shown that steroid hormones, such as DHEA, have the potential to act as immunostimulatory factors in vivo. Inhibiting the conversion of DHEAS to DHEA by SS enzyme leads to an anti-inflammatory effect.
Suitters
A J
AJ
Celltech Therapeutics Ltd, Slough, Berkshire, UK.
Shaw
S
S
Wales
M R
MR
Porter
J P
JP
Leonard
J
J
Woodger
R
R
Brand
H
H
Bodmer
M
M
Foulkes
R
R
D000276:Adjuvants, Immunologic; D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003687:Dehydroepiandrosterone / Q000276:immunology*; D019314:Dehydroepiandrosterone Sulfate / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000517:prevention & control; D003907:Dexamethasone / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010081:Oxazolone / Q000276:immunology; D043266:Steryl-Sulfatase
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; C088768:estrone-3-O-sulfamate; D010081:Oxazolone; D004970:Estrone; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D003907:Dexamethasone; D001192:Arylsulfatases; D043266:Steryl-Sulfatase