RESEARCH - TNF inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in RA synovial cells

[Guest guest]

Arthritis Rheum. 2005 Jun 2;52(6):1721-1729 [Epub ahead of print]

Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate

(DHEAS) to DHEA in rheumatoid arthritis synovial cells: A prerequisite for

local androgen deficiency.

Weidler C, Struharova S, Schmidt M, Ugele B, Scholmerich J, Straub RH.

University Hospital Regensburg, Regensburg, Germany.

OBJECTIVE: Use of anti-tumor necrosis factor (anti-TNF) antibody therapy in

rheumatoid arthritis (RA) has expanded our understanding of possible

mechanisms by which this treatment reduces inflammation. Beyond its effects

on local immune responses, anti-TNF treatment may also modulate the local

hormone supply. Because androgens are thought to inhibit immune responses,

their presence in inflamed tissue is an additional important

antiinflammatory factor. METHODS: We investigated conversion of the

ubiquitous dehydroepiandrosterone sulfate (DHEAS), the biologically inactive

precursor of DHEA, to the androgen DHEA in mixed synovial cells from

patients with RA and patients with osteoarthritis (OA), making use of

thin-layer chromatography and phosphorimaging. Using immunohistochemical

analysis, we detected the key enzyme, steroid sulfatase. RESULTS:

DHEAS-to-DHEA conversion in synovial cells from patients with RA was

significantly lower than that in synovial cells from patients with OA (mean

+/- SEM 3.3 +/- 0.5% versus 6.0 +/- 0.9% of applied (3)H-DHEAS per 10(6)

synovial cells; P = 0.042). In RA, but not in OA, the level of converted

(3)H-DHEA was inversely correlated with the density of synovial macrophages

(for RA, R(rank) = -0.725, P = 0.005; for OA, R(rank) = 0.069, P not

significant [NS]) and T cells (for RA, R(rank) = -0.621, P = 0.024; for OA,

R(rank) = 0.247, P NS). Double immunohistochemistry analysis revealed that

steroid sulfatase was located mainly in synovial macrophages but was also

observed in fibroblasts. Neutralization of TNF largely up-regulated the

conversion of DHEAS to DHEA in RA, but not in OA. A similar neutralizing

effect was observed with polyclonal human immunoglobulins; this effect is

most probably mediated via TNF neutralization at low TNF concentrations.

CONCLUSION: These data indicate that TNF inhibits the conversion of DHEAS to

DHEA in RA synovial cells. Because androgens are antiinflammatory mediators,

TNF-induced inhibition of the local androgen supply is a supplementary

proinflammatory factor. Consequently, anti-TNF strategies may also exert

their positive effects by increasing tissue androgens.

PMID: 15934093

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5934093 & dopt=Abstract

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org