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
Telefon: +81 (88) 633 71 77 ·
Fax: +81 (88) 631 26 30
eMail: uemura@clin.med.tokushima-u.ac.jp