Abstract
We studied the effects of hormone replacement therapy (HRT) with estrogen on postmenopausal changes in the production of bone-resorbing cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα). Both cytokines were measured in the supernatants of lipopolysaccharide (LPS)-stimulated whole-blood cells from 72 untreated and 44 HRT-treated women by ELISA. The levels of IL-1β were significantly higher in women in their 40 s and 50 s and in postmenopausal women than in women in their teens, 20 s and 30 s, while the levels of TNFα did not show any changes related to age. Both levels in HRT-treated women were significantly lower than those in untreated women at almost every postmenopausal stage. In a prospective study, HRT induced significant declines in both levels. These results show that estrogen decreases the accelerated production of IL-1β and reduces the production of TNFα in postmenopausal women at each postmenopausal stage, even in late-postmenopausal women.
Key words
HRT - Postmenopause - IL-1β - TNFα - Whole-blood cells
References
-
1
Khorrmann O, Yeung M, Vu L, Yen S SC.
Effects of [norleucine27] growth hormone-releasing hormone (GHRH) (1 - 29)-NH2 administration on the immune system of aging men and women.
J Clin Endocrinol Metab.
1997;
82
3590-3596
-
2
Straub R H, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B.
Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.
J Clin Endocrinol Metab.
1998;
83
2012-2017
-
3
Jilka R L, Hangoc G, Girasole G, Passeri G, Williams D C, Abrams J S, Boyce B, Broxmeyer H, Manolagas S C.
Increased osteoclast development after estrogen loss: mediation by interleukin-6.
Science.
1992;
257
88-91
-
4
Kitazawa R, Kimble R B, Vannice J L, Kung V T, Pacifici R.
Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice.
J Clin Invest.
1994;
94
2397-2406
-
5
Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan G A, Costantini F.
Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.
EMBO J.
1994;
13
1189-1196
-
6
Lorenzo J A, Naprta A, Rao Y, Alander C, Glaccum M, Widmer M, Gronowicz G, Kalinowski J, Pilbeam C C.
Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy.
Endocrinology.
1998;
139
3022-3025
-
7
Ammann P, Rizzoli R, Bonjour J P, Bourrin S, Meyer J M, Vassalli P, Garcia I.
Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency.
J Clin Invest.
1997;
99
1699-1703
-
8
Pacifici R, Rifas L, McCracken R, Vered I, McMurtry C, Avioli L V, Peck W A.
Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin-1 release.
Proc Natl Acad Sci USA.
1989;
86
2398-2402
-
9
Pacifici R.
Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis.
J Bone Min Res.
1996;
11
1043-1051
-
10
Manolagas S C, Jilka R L.
Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis.
N Engl J Med.
1995;
332
305-311
-
11
Zheng S X, Vrindts Y, Lopez M, De Groote D, Zangerle P F, Collette J, Franchimont N, Geenen V, Albert A, Reginster J Y.
Increase in cytokine production (IL-1β, IL-6, TNF-αl but not IFN-g, GM-CSF or LIF) by stimulated whole-blood cells in postmenopausal osteoporosis.
Maturitas.
1997;
6
63-71
-
12
Cohen-Solal M E, Boitte F, Bernard-Poenaru O, Denne M A, Graulet A M, Brazier M, De Vernejoul M C.
Increased bone resorbing activity of peripheral monocyte culture supernatants in elderly women.
J Clin Endocrinol Metab.
1998;
83
1687-1690
-
13
Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli L V.
Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells.
Proc Natl Acad Sci USA.
1991;
88
5134-5138
-
14
Koka S, Petro T M, Reinhardt R A.
Estrogen inhibits interleukin-1β-induced interleukin-6 production by human osteoblast-like cells.
J Interferon Cytokine Res.
1998;
18
479-483
-
15
Zarrabeitia M T, Riancho J A, Amado J A, Napal J, Gonzalez-Macias J.
Cytokine production by peripheral blood cells in postmenopausal osteoporosis.
Bone Miner.
1991;
14
161-167
-
16
Hustmyer F G, Walker E, Yu X P, Girasole G, Sakagami Y, Peacock M, Manolagas S C.
Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis.
J Bone Miner Res.
1993;
8
51-59
-
17
Abrahamsen B, Bendtzen K, Beck-Nielsen H.
Cytokines and T-lymphocyte subsets in healthy post-menopausal women: estrogen retards bone loss without affecting the release of IL-1 or IL-1ra.
Bone.
1997;
20
251-258
-
18
De Groote D, Zangerle P F, Gevaert Y, Fassotte M F, Beguin Y, Noizat-Pirenne F, Pirenne J, Gathy R, Lopez M, Dehart I. et al .
Direct stimulation of cytokines (IL-1β and TNF-α, IL-6, IL-2, IFN-g and GM-CSF) in whole blood. Comparisons with isolated PBMC stimulation.
Cytokine.
1992;
4
239-248
-
19
Ligthart G J, Corberand J X, Fournier C, Galanaud P, Hijmans W, Kennes B, Muller-Hermelink H K, Steinmann G G.
Admission criteria for immunogerontological studies in man: the SENIEUR protocol.
Mech Ageing Dev.
1984;
28
47-55
-
20
Kamada M, Maeda N, Maegawa M, Mori H, Yamamoto S, Aono T, Muraguchi M, Ohmoto Y, Futaki S, Ogushi F, Sone S, Kanayama H, Kagawa S, Koide S S.
Detection of immunoglobulin binding factor by enzyme-linked immunosorbent assay using two monoclonal antibodies.
Biochem Mol Biol Internatl.
1994;
34
837-844
-
21
Kawane T, Takahashi S, Saitoh H, Okamoto H, Kubodera N, Horiuchi N.
Anabolic effects of recombinant human parathyroid hormone (1 - 84) and synthetic human parathyroid hormone (1 - 34) on the mandibles of osteopenic ovariectomized rats with maxillary molar extraction.
Horm Metab Res.
2002;
34
293-302
-
22
Jimi E, Nakamura I, Ikebe T, Akiyama S, Takahashi N, Suda T.
Activation of NF-kB is involved in the survival of osteoclasts promoted by interleukin-1.
J Biol Chem.
1998;
273
8799-8805
-
23
Kimble R B, Srivastava S, Ross F P, Matayoshi A, Pacifici R.
Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1 and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production.
J Biol Chem.
1996;
271
28 890-28 897
-
24
Sarma U, Flanagan-AM .
Macrophage colony-stimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures.
Blood.
1996;
188
2531-2540
-
25
Sarma U, Edwards M, Motoyoshi K, Flanagan A M.
Inhibition of bone resorption by 17βradiol in human bone marrow cultures.
J Cell Physiol.
1998;
175
99-108
-
26
Cohen-Solal M E, Graulet A M, Denne M A, Gueris J, Baylink D, de Vernejoul M C.
Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines.
J Clin Endocrinol Metab.
1993;
77
1648-1653
-
27
Cohen-Solal M E, Graulet A M, Gueris J, Denne M A, Bergot C, Morieux C, Sedel L, Kuntz D, De Vernejoul M C.
Bone resorption at the femoral neck is dependent on local factors in nonosteoporotic late postmenopausal women: an in vitro-in vivo study.
J Bone Miner Res.
1995;
10
307-314
-
28
Matsushima K, Procopio A, Abe H, Seala G, Orraldo J R, Oppenheim J J.
Production of interleukin 1 activity by normal human peripheral blood B lymphocytes.
J Immunol.
1985;
135
1132-1136
-
29
Scala G, Allavena P, Djeu J Y, Kasahara T, Ortaldo J R, Herberman R B, Oppenheim J J.
Human large granular lymphocytes are potent producers of interleukin-1.
Nature.
1984;
309
56-59
-
30
Kimble R B, Matayoshi A B, Vannice J L, Kung V T, Williams C, Pacifici R.
Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period.
Endocrinology.
1995;
1136
3054-3061
-
31
Garnero P, Sornay-Rendu E, Chapuy M C, Delmas P D.
Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
J Bone Miner Res.
1996;
11
337-349
Hirokazu Uemura, M.D., PhD
Department of Obstetrics and Gynecology · University of Tokushima · School of Medicine
3-18-15 Kuramoto-cho · Tokushima · 770-8503 Japan
Phone: +81 (88) 633 71 77 ·
Fax: +81 (88) 631 26 30
Email: uemura@clin.med.tokushima-u.ac.jp