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Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency.
Arthritis Rheum. 2005 Jun; 52(6):1721-9.AR

Abstract

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.

Authors+Show Affiliations

University Hospital Regensburg, Regensburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15934093

Citation

Weidler, Claudia, et al. "Tumor Necrosis Factor Inhibits Conversion of Dehydroepiandrosterone Sulfate (DHEAS) to DHEA in Rheumatoid Arthritis Synovial Cells: a Prerequisite for Local Androgen Deficiency." Arthritis and Rheumatism, vol. 52, no. 6, 2005, pp. 1721-9.
Weidler C, Struharova S, Schmidt M, et al. Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. Arthritis Rheum. 2005;52(6):1721-9.
Weidler, C., Struharova, S., Schmidt, M., Ugele, B., Schölmerich, J., & Straub, R. H. (2005). Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. Arthritis and Rheumatism, 52(6), 1721-9.
Weidler C, et al. Tumor Necrosis Factor Inhibits Conversion of Dehydroepiandrosterone Sulfate (DHEAS) to DHEA in Rheumatoid Arthritis Synovial Cells: a Prerequisite for Local Androgen Deficiency. Arthritis Rheum. 2005;52(6):1721-9. PubMed PMID: 15934093.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. AU - Weidler,Claudia, AU - Struharova,Sona, AU - Schmidt,Martin, AU - Ugele,Bernhard, AU - Schölmerich,Jürgen, AU - Straub,Rainer H, PY - 2005/6/4/pubmed PY - 2005/9/16/medline PY - 2005/6/4/entrez SP - 1721 EP - 9 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 52 IS - 6 N2 - 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. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/15934093/Tumor_necrosis_factor_inhibits_conversion_of_dehydroepiandrosterone_sulfate__DHEAS__to_DHEA_in_rheumatoid_arthritis_synovial_cells:_a_prerequisite_for_local_androgen_deficiency_ L2 - https://doi.org/10.1002/art.21112 DB - PRIME DP - Unbound Medicine ER -