Adipocytes Enhance the Proliferation of Human Leiomyoma Cells Via TNF-α Proinflammatory Cytokine



Obesity is a well-documented risk factor for uterine leiomyoma with a major impact on women health and health care system of the nation. Obesity is associated with increased secretion of adipokines that significantly influence growth and proliferation of tumor stroma and malignant cells. Adipokines, such as tumor necrosis factor α (TNF-α), are produced in the adipose tissue with concomitant expression in other organs and tissues. Increased and sustained cytokine production is associated with alterations in cell growth and differentiation. We, therefore, explored the influence of human adipocytes (SW872 cells)–mediated biological humoral factors on human uterine leiomyoma (HuLM) cells.


We measured cell proliferation and expression of cell-proliferating proteins (proliferating cell nuclear antigen [PCNA], cyclin D1, and B-cell lymphoma 2 [BCL-2]) in human leiomyoma cells cocultured with SW872 cells. SW872-conditioned media was neutralized for TNF-α and proliferation of HuLM cells was observed along with antiapoptotic marker, BCL-2, using Western immunoblot. Results: We found that both SW872-conditioned media and coculture with SW872 cells increased HuLM cell proliferation significantly (P < .05). We determined that this effect was associated with the upregulation of specific markers for proliferation, such as PCNA, cyclin D1, and BCL-2 (P < .05). Furthermore, the addition of neutralizing antibodies, anti-TNF-α, to SW872-conditioned media reversed the proliferation of leiomyoma cells and induced apoptosis as indicated by the reduced expression of antiapoptotic marker BCL-2. Conclusions: SW872 cells secrete TNF-α, which is associated with a proliferative gene profile in HuLM cells and may play a role in initiation and/or progression of uterine leiomyoma.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111(8):1037–1054.

  2. 2.

    Marshall LM, Spiegelman D, Barbieri RL, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol. 1997;90(6):967–973.

  3. 3.

    Othman EE, Al-Hendy A. Molecular genetics and racial disparities of uterine leiomyomas. Best Pract Res Clin Obstet Gynaecol. 2008;22(4):589–601.

  4. 4.

    Wise LA, Palmer JR, Stewart EA, Rosenberg L. Age specific incidence rates for self-reported uterine leiomyomata in the Black Women’s health study. Obstet Gynecol. 2005;105(3):563–568.

  5. 5.

    Schwartz SM. Epidemiology of uterine leiomyoma. Clin Obstet Gynecol. 2001;44(2):316–326.

  6. 6.

    Sato F, Nishi M, Kudo R, Miyake H. Body fat distribution and uterine leiomyomas. J Epidemiol. 1998;8(3):176–180.

  7. 7.

    Shikora SA, Niloff JM, Bistrian BR, Forse RA, Blackburn GL. Relationship between obesity and uterine leiomyomata. Nutrition. 1991;7(4):251–255.

  8. 8.

    Farinati F, Cardin R, Cassaro M, et al. Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway. Eur J Cancer Prev. 2008;17(3):195–200.

  9. 9.

    Festa A, D’Agostino Jr R, Williams K, et al. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001;25(10):1407–1415.

  10. 10.

    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95(5):2409–2415.

  11. 11.

    Inadera H. The usefulness of circulating adipokine levels for the assessment of obesity-related health problems. Int J Med Sci. 2008;5(5):248–262.

  12. 12.

    Rajala MW, Scherer PE. Minireview: the adipocyte-at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144(9):3765–3773.

  13. 13.

    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91.

  14. 14.

    Samad F, Yamamoto K, Pandey M, Loskutoff DJ. Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol Med. 1997;3(1):37–48.

  15. 15.

    Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–850.

  16. 16.

    Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA. 2003;100(12):7265–7270.

  17. 17.

    Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548–2556.

  18. 18.

    Dandona P, Weinstock R, Thusu K, Abdel-rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab. 1998;83(8):2907–2910.

  19. 19.

    Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol. 2005;25(10):2062–2068.

  20. 20.

    Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw. 1996;7(2):93–124.

  21. 21.

    Parker WH. Uterine myomas: management. Fertil Steril. 2007;88(2):255–271.

  22. 22.

    Sozen I, Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil Steril. 2002;78(1):1–12.

  23. 23.

    Richardson MA, Berg DT, Johnston PA, McClure D, Grinnell BW. Human liposarcoma cell line, SW872, secretes cholesteryl ester transfer protein in response to cholesterol. J Lipid Res. 1996;37(5):1162–1166.

  24. 24.

    Izem L, Morton RE. Cholesteryl ester transfer protein biosynthesis and cellular cholesterol homeostasis are tightly interconnected. J Biol Chem. 2001;276(28):26534–26541.

  25. 25.

    Vassiliou G, Benoist F, Lau P, Kavaslar GN, McPherson R. The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. J Biol Chem. 2001;276(52):48823–48830.

  26. 26.

    Oppenheim JJ, Feldmann M. Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity. New York, NY: Academic Press; 2001:3–20.

  27. 27.

    Varella-Garcia M, Chen L, Zheng X, Yu L, Dixon D. Karyotypic characteristics of human uterine leiomyoma and myometrial cell lines following telomerase induction. Cancer Genet Cytogenet. 2006;170(1):71–75.

  28. 28.

    Frühbeck G. The adipose tissue as a source of vasoactive factors. Curr Med Chem Cardiovasc Hematol Agents. 2004;2(3):197–208.

  29. 29.

    Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92(3):347–355.

  30. 30.

    Wang B, Trayhurn P. Acute and prolonged effects of TNF-alpha on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Endocrinology. 2006;452(4):418–427.

  31. 31.

    Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95(5):2111–2119.

  32. 32.

    Maachi M, Piéroni L, Bruckert E, et al. Systemic low-grade inflammation is related to circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women. Int J Obes. 2004;28(8):993–997.

  33. 33.

    Lukasiak S, Schiller C, Oehlschlaeger P, et al. Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon. Oncogene. 2008;27(46):6068–6074.

  34. 34.

    Wang D, DuBois RN. Pro-inflammatory prostaglandins and progression of colorectal cancer. Cancer Lett. 2008;267(2):197–203.

  35. 35.

    Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J(Clin Res Ed). 1986;293(6543):359–362.

  36. 36.

    Matsuo H, Kurachi O, Shimomura Y, Samoto T, Maruo T. Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma. Oncology. 1999;57(suppl 2):49–58.

  37. 37.

    Danforth DN Jr, Sgagias MK. Tumour necrosis factor-α modulates oestradiol responsiveness of MCF-7 breast cancer cells in vitro. J Endocrinol. 1993;138(3):517–528.

  38. 38.

    Terranova PF, Hunter VJ, Roby KF, Hunt JS. Tumor necrosis factor-α in the female reproductive tract. Proc Soc Exp Biol Med. 1995;209(4):325–342.

  39. 39.

    Tilg H, Moschen R. Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases. Clin Sci. 2008;114(4):275–288.

  40. 40.

    Tsigos C, Kyrou I, Chala E, et al. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metabolism. 1999;48(10):1332–1335.

  41. 41.

    Marfella R, Esposito K, Siniscalchi M, et al. Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care. 2004;27(1):47–52.

  42. 42.

    Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G. The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol. 2001;80(8):554–561.

  43. 43.

    Moore AB, Yu L, Swartz CD, et al. Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture. Cell Commun Signal. 2010;8:10.

Download references

Author information

Correspondence to Ayman Al-Hendy MD, PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nair, S., Al-Hendy, A. Adipocytes Enhance the Proliferation of Human Leiomyoma Cells Via TNF-α Proinflammatory Cytokine. Reprod. Sci. 18, 1186–1192 (2011) doi:10.1177/1933719111408111

Download citation


  • obesity
  • uterine leiomyoma
  • coculture
  • adipokines