Archives of Dermatological Research

, Volume 311, Issue 7, pp 563–571 | Cite as

Alterations in IL-4, IL-10 and IFN-γ levels synergistically decrease lipid content and protein expression of FAS and mature SREBP-1 in human sebocytes

  • Jihye Shin
  • Kun-pyo Kim
  • Hee Yoon Ahn
  • Bongjoon Kim
  • Yunhi ChoEmail author
Concise Communication


When anti-acne alternatives from dietary and plant sources are ingested, systemic alterations of interleukin (IL)-4, IL-10, IL-12 and interferon (IFN)-γ, individually or simultaneously, are induced at a 0.1–10.0-fold (×) range of normal physiological concentrations (1×). However, little is known about the effects of these cytokines on excess sebum, a pathophysiological factor of acne development. In this study, human sebocytes were treated with 0.1–10.0× of IL-4, IL-10, IL-12 and IFN-γ for 3 or 5 days to elucidate the effects on lipid content. Treatment with individual cytokines decreased the lipid content at specific concentrations rather than in a concentration-dependent manner. Specifically, 5.0× of IL-4, 5.0× of IFN-γ (5.0IFN), and 0.5×, 5.0× and 10.0× of IL-10 for 3 days, and 0.5× of IL-4 (0.5IL4) for 5 days decreased lipid content to 87.6–93.0% of the control. Treatment with other concentrations of IL-4, IL-10 and IFN-γ, and 0.1–10.0× of IL-12 did not alter lipid content. Combined treatment with 0.5IL4, 5.0IFN and 0.5× of IL-10 for 3 or 5 days decreased the lipid content more than each individual treatment. However, this effect was more evident after 3 days, in parallel with decreased levels of triglycerides, cholesterol esters and free fatty acids, the major lipid compositions of sebocytes, and decreased protein expression of fatty acid synthase (FAS) and mature sterol response element-binding protein-1 (SREBP-1), the lipogenesis-related factors, without altered cell proliferation. We demonstrated that suppressed IL-4 and IL-10 with enhanced IFN-γ synergistically decreased lipid content and protein expression of FAS and mature SREBP-1 in human sebocytes.


Sebocytes Cytokines Synergism Lipid content FAS Mature SREBP-1 



This study was supported by CJ Foods R & D Center, CJ CheilJedang Corporation in Suwon-si, Gyeongggi-do, Republic of Korea (KHU Grant No. 20150943).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Agnello D, Lankford CSR, Bream J, Morinobu A, Gadina M, O’Shea JJ, Frucht DM (2003) Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol 23:147–161. CrossRefPubMedGoogle Scholar
  2. 2.
    Antiga E, Verdelli A, Bonciani D, Bonciolini V, Caproni M, Fabbri P (2015) Acne: a new model of immune-mediated chronic inflammatory skin disease. G Ital Dermatol Venereol 150:247–254PubMedGoogle Scholar
  3. 3.
    Caillon F, O’Connell M, Eady EA, Jenkins GR, Cove JH, Layton AM, Mountford AP (2010) Interleukin-10 secretion from CD14+ peripheral blood mononuclear cells is downregulated in patients with acne vulgaris. Br J Dermatol 162:296–303. CrossRefPubMedGoogle Scholar
  4. 4.
    Cendrowski J, Mamińska A, Miaczynska M (2016) Endocytic regulation of cytokine receptor signaling. Cytokine Growth factor Rev 32:63–73. CrossRefPubMedGoogle Scholar
  5. 5.
    Choi JJ, Park MY, Lee HJ, Yoon DY, Lim Y, Hyun JW, Zouboulis CC, Jin M (2012) TNF-alpha increases lipogenesis via JNK and PI3K/Akt pathways in SZ95 human sebocytes. J Dermatol Sci 65:179–188. CrossRefPubMedGoogle Scholar
  6. 6.
    Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777CrossRefGoogle Scholar
  7. 7.
    Georgel P, Crozat K, Lauth X, Makrantonaki E, Seltmann H, Sovath S, Hoebe K, Du X, Rutschmann S, Jiang ZF, Bigby T, Nizet V, Zouboulis CC, Beutler B (2005) A Toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria. Infect Immun 73:4512–4521. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gollnick HP (2015) From new findings in acne pathogenesis to new approaches in treatment. J Eur Acad Dermatol Venereol 29(Suppl 5):1–7. CrossRefPubMedGoogle Scholar
  9. 9.
    Gong Y, Wei SH, Zhang MN, Jin X, Hou BK, Wang D (2010) Serum interferon-gamma/interleukin-4 imbalance in patients with Eales’ disease. Clin Exp Optom 93:228–232. CrossRefPubMedGoogle Scholar
  10. 10.
    Grange PA, Weill B, Dupin N, Batteux F (2010) Does inflammatory acne result from imbalance in the keratinocyte innate immune response? Microbes Infect 12:1085–1090. CrossRefPubMedGoogle Scholar
  11. 11.
    Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK (1999) Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400:378–382. CrossRefPubMedGoogle Scholar
  12. 12.
    Jung JY, Kwon HH, Hong JS, Yoon JY, Park MS, Jang MY, Suh DH (2014) Effect of dietary supplementation with omega-3 fatty acid and gamma-linolenic acid on acne vulgaris: a randomised, double-blind, controlled trial. Acta Dermato-Venereol 94:521–525. CrossRefGoogle Scholar
  13. 13.
    Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ (2005) Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo. Am J Pathol 166:1691–1699CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Karadag AS, Ertugrul DT, Bilgili SG, Takci Z, Akin KO, Calka O (2012) Immunoregulatory effects of isotretinoin in patients with acne. Br J Dermatol 167:433–435. CrossRefPubMedGoogle Scholar
  15. 15.
    Kasumagic-Halilovic E, Prohic A, Karamehic J (2010) Serum concentrations of interferon-gamma (IFN-g) in patients with alopecia areata: correlation with clinical type and duration of the disease. Med Arh 64:212–214PubMedGoogle Scholar
  16. 16.
    Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G (2013) Cytokine levels in the serum of healthy subjects. Med Inflamm 2013:434010. CrossRefGoogle Scholar
  17. 17.
    Krycer JR, Sharpe LJ, Luu W, Brown AJ (2010) The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 21:268–276. CrossRefPubMedGoogle Scholar
  18. 18.
    Li ZJ, Park SB, Sohn KC, Lee Y, Seo YJ, Kim CD, Kim YS, Lee JH, Im M (2013) Regulation of lipid production by acetylcholine signalling in human sebaceous glands. J Dermatol Sci 72:116–122. CrossRefPubMedGoogle Scholar
  19. 19.
    Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK, Sztein MB (2004) Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun 72:5630–5637. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Mastrofrancesco A, Ottaviani M, Cardinali G, Flori E, Briganti S, Ludovici M, Zouboulis CC, Lora V, Camera E, Picardo M (2017) Pharmacological PPARgamma modulation regulates sebogenesis and inflammation in SZ95 human sebocytes. Biochem Pharmacol 138:96–106. CrossRefPubMedGoogle Scholar
  21. 21.
    Melnik B (2012) Dietary intervention in acne: attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol 4:20–32. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, McDowell A, Seltmann H, Patrick S, Zouboulis CC, Kemeny L (2006) Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. Microbes Infect 8:2195–2205. CrossRefPubMedGoogle Scholar
  23. 23.
    Nakajima M, Hiroshi I, Shirasawa T, Miyauchi H, Takatsu Z, Yamazaki N, Teraguchi S, Hayasawa H (1999) Oral administration of lactoferrin enhances the productions of IFN-γ and IL-10 in spleen cells cultured with Concanavalin A or lipopolysaccharide. Biomed Res 20:27–33. CrossRefGoogle Scholar
  24. 24.
    Nielsen AA, Jorgensen LG, Nielsen JN, Eivindson M, Gronbaek H, Vind I, Hougaard DM, Skogstrand K, Jensen S, Munkholm P, Brandslund I, Hey H (2005) Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn’s disease compared with omega-6 fatty acids. Aliment Pharmacol Ther 22:1121–1128. CrossRefPubMedGoogle Scholar
  25. 25.
    Nikkari T (1974) Comparative chemistry of sebum. J Invest Dermatol 62:257–267CrossRefPubMedGoogle Scholar
  26. 26.
    Oh JE, Kim RH, Shin KH, Park NH, Kang MK (2011) DeltaNp63alpha protein triggers epithelial-mesenchymal transition and confers stem cell properties in normal human keratinocytes. J Biol Chem 286:38757–38767. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Oláh A, Tóth BI, Borbíró I, Sugawara K, Szöllõsi AG, Czifra G, Pál B, Ambrus L, Kloepper J, Camera E, Ludovici M, Picardo M, Voets T, Zouboulis CC, Paus R, Bíró T (2014) Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Invest 124:3713–3724. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ottaviani M, Camera E, Picardo M (2010) Lipid mediators in acne. Mediat Inflamm 2010:1–6. CrossRefGoogle Scholar
  29. 29.
    Park HJ, Lee SJ, Kim SH, Han J, Bae J, Kim SJ, Park CG, Chun T (2011) IL-10 inhibits the starvation induced autophagy in macrophages via class I phosphatidylinositol 3-kinase (PI3K) pathway. Mol Immunol 48:720–727. CrossRefPubMedGoogle Scholar
  30. 30.
    Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cel 146:408–420. CrossRefGoogle Scholar
  31. 31.
    Rey AA, Purrio M, Viveros MP, Lutz B (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsycho Pharmacol 37:2624–2634. CrossRefGoogle Scholar
  32. 32.
    Rosignoli C, Nicolas JC, Jomard A, Michel S (2003) Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo. Exp Dermatol 12:480–489CrossRefPubMedGoogle Scholar
  33. 33.
    Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, Parolaro D, Massi P (2005) The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol 159:97–105. CrossRefPubMedGoogle Scholar
  34. 34.
    Smith KR, Thiboutot DM (2008) Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe? J Lipid Res 49:271–281. CrossRefPubMedGoogle Scholar
  35. 35.
    Spangler JB, Noraga I, Mendoza JL, Garcia KC (2015) Insights into cytokine-receptor interactions from cytokine engineering. Annu Rev Immunol 33:139–167. CrossRefPubMedGoogle Scholar
  36. 36.
    Su XD, Yu YP, Zhong Y, Giannopoulou EG, Hu XY, Liu H, Cross JR, Ratsch G, Rice CM, Ivashkiv LB (2015) Interferon-gamma regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol 16:838–849. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Van Aller GS, Carson JD, Tang W, Peng H, Zhao L, Copeland RA, Tummino PJ, Luo LS (2011) Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochem Biophys Res Commun 406:194–199. CrossRefPubMedGoogle Scholar
  38. 38.
    Volpert OV, Fong T, Koch AE, Peterson JD, Waltenbaugh C, Tepper RI, Bouck NP (1998) Inhibition of angiogenesis by interleukin 4. J Exp Med 188:1039–1046CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Weichhart T, Saemann MD (2008) The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis 67(Suppl 3 iii):70–74. CrossRefGoogle Scholar
  40. 40.
    Won TJ, Kim B, Song DS, Lim YT, Oh ES, Lee DI, Park ES, Min H, Park SY, Hwang KW (2011) Modulation of Th1/Th2 balance by Lactobacillus strains isolated from Kimchi via stimulation of macrophage cell line J774A.1 in vitro. J Food Sci 76:H55–H61. CrossRefPubMedGoogle Scholar
  41. 41.
    Xue K, Liu H, Jian Q, Liu B, Zhu D, Zhang M, Gao L, Li C (2013) Leptin induces secretion of pro-inflammatory cytokines by human keratinocytes in vitro–a possible reason for increased severity of psoriasis in patients with a high body mass index. Exp Dermatol 22:406–410. CrossRefPubMedGoogle Scholar
  42. 42.
    Yoon JY, Kwon HH, Min SU, Thiboutot DM, Suh DH (2013) Epigallocatechin-3-gallate improves acne in humans by modulating intracellular molecular targets and inhibiting P. acnes. J Invest Dermatol 133:429–440. CrossRefPubMedGoogle Scholar
  43. 43.
    Zouboulis CC (2004) Acne and sebaceous gland function. Clin Dermatol 22:360–366. CrossRefPubMedGoogle Scholar
  44. 44.
    Zouboulis CC, Korge B, Akamatsu H, Xia LQ, Schiller S, Gollnick H, Orfanos CE (1991) Effects of 13-cis-retinoic acid, all-trans-retinoic acid, and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro. J Invest Dermatol 96:792–797CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Nutrition, Graduate School of East–West Medical ScienceKyung Hee UniversityYongin-siRepublic of Korea
  2. 2.CJ Foods R & D CenterCJ CheilJedang CorporationSuwon-siRepublic of Korea

Personalised recommendations