Research Article| Volume 65, ISSUE 3, P179-188, March 2012

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TNF-α increases lipogenesis via JNK and PI3K/Akt pathways in SZ95 human sebocytes

Published:February 03, 2012DOI:



      Tumor necrosis factor-alpha (TNF-α) is an important pathophysiologic factor involved in the development of acne. However, its role is unclear.


      To explore the lipogenic effect by TNF-α and possible molecular mechanisms in sebocyte.


      Using SZ95 human sebocytes, lipid formation by TNF-α was assessed by Oil Red O, Nile Red staining and thin layer chromatography (TLC). Expression of lipogenic genes and activation of mitogen-activated protein kinase as well as Akt were examined by real-time polymerase chain reaction and/or Western blot analysis. Activation of peroxisome proliferator-activated receptor (PPAR) was evaluated by luciferase assay using PPAR response element containing reporter plasmids. Involvement of c-Jun N-terminal kinase (JNK) and Akt in TNF-α-induced lipogenesis was investigated by molecule specific small interfering RNA and inhibitors.


      TNF-α treatment significantly increased formation of lipid droplets in accordance with up-regulated expression of FAS and activation of SREBP-1, but not PPARs. Suppression of phosphorylated JNK by the JNK inhibitor SP600125 greatly diminished TNF-α-induced expression of FAS and SREBP-1. TNF-α could not induce both expression of lipogenic proteins and lipid synthesis when Akt expression was attenuated with siRNA.


      TNF-α induces lipogenesis in SZ95 human sebocytes through the JNK and phosphoinositide-3-kinase/Akt pathways. These results will be valuable in developing therapeutic strategies for control of seborrhea and acne.


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        • Smith K.R.
        • Thiboutot D.M.
        Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe?.
        J Lipid Res. 2008; 49: 271-281
        • Schneider M.R.
        • Paus R.
        Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion.
        Int J Biochem Cell Biol. 2010; 42: 181-185
        • Zouboulis C.C.
        • Chen W.C.
        • Thornton M.J.
        • Qin K.
        • Rosenfield R.
        Sexual hormones in human skin.
        Horm Metab Res. 2007; 39: 85-95
        • Smith T.M.
        • Cong Z.
        • Gilliland K.L.
        • Clawson G.A.
        • Thiboutot D.M.
        Insulin-like growth factor-1 induces lipid production in human SEB-1 sebocytes via sterol response element-binding protein-1.
        J Invest Dermatol. 2006; 126: 1226-1232
        • Makrantonaki E.
        • Vogel K.
        • Fimmel S.
        • Oeff M.
        • Seltmann H.
        • Zouboulis C.C.
        Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro.
        Exp Gerontol. 2008; 43: 939-946
        • Alestas T.
        • Ganceviciene R.
        • Fimmel S.
        • Muller-Decker K.
        • Zouboulis C.C.
        Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands.
        J Mol Med. 2006; 84: 75-87
        • Zouboulis Ch C.
        • Saborowski A.
        • Boschnakow A.
        Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production.
        Dermatology. 2005; 210: 36-38
        • Chen W.
        • Yang C.C.
        • Sheu H.M.
        • Seltmann H.
        • Zouboulis C.C.
        Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes.
        J Invest Dermatol. 2003; 121: 441-447
        • Harrison W.J.
        • Bull J.J.
        • Seltmann H.
        • Zouboulis C.C.
        • Philpott M.P.
        Expression of lipogenic factors galectin-12, resistin, SREBP-1, and SCD in human sebaceous glands and cultured sebocytes.
        J Invest Dermatol. 2007; 127: 1309-1317
        • Cho M.C.
        • Lee K.
        • Paik S.G.
        • Yoon D.Y.
        Peroxisome proliferators-activated receptor (PPAR) modulators and metabolic disorders.
        PPAR Res. 2008; : 679137
        • Trivedi N.R.
        • Cong Z.
        • Nelson A.M.
        • Albert A.J.
        • Rosamilia L.L.
        • Sivarajah S.
        • et al.
        Peroxisome proliferator-activated receptors increase human sebum production.
        J Invest Dermatol. 2006; 126: 2002-2009
        • Hong I.
        • Lee M.H.
        • Na T.Y.
        • Zouboulis C.C.
        • Lee M.O.
        LXRalpha enhances lipid synthesis in SZ95 sebocytes.
        J Invest Dermatol. 2008; 128: 1266-1272
        • Nagy I.
        • Pivarcsi A.
        • Kis K.
        • Koreck A.
        • Bodai L.
        • McDowell A.
        • et al.
        Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes.
        Microbes Infect. 2006; 8: 2195-2205
        • Kim J.
        • Ochoa M.T.
        • Krutzik S.R.
        • Takeuchi O.
        • Uematsu S.
        • Legaspi A.J.
        • et al.
        Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.
        J Immunol. 2002; 169: 1535-1541
        • Rossol S.
        • Voth R.
        • Brunner S.
        • Muller W.E.
        • Buttner M.
        • Gallati H.
        • et al.
        Corynebacterium parvum (Propionibacterium acnes): an inducer of tumor necrosis factor-alpha in human peripheral blood mononuclear cells and monocytes in vitro.
        Eur J Immunol. 1990; 20: 1761-1765
        • Graham G.M.
        • Farrar M.D.
        • Cruse-Sawyer J.E.
        • Holland K.T.
        • Ingham E.
        Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL.
        Br J Dermatol. 2004; 150: 421-428
        • Jeremy A.H.
        • Holland D.B.
        • Roberts S.G.
        • Thomson K.F.
        • Cunliffe W.J.
        Inflammatory events are involved in acne lesion initiation.
        J Invest Dermatol. 2003; 121: 20-27
        • Zouboulis C.C.
        • Seltmann H.
        • Neitzel H.
        • Orfanos C.E.
        Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95).
        J Invest Dermatol. 1999; 113: 1011-1020
        • Smith T.M.
        • Gilliland K.
        • Clawson G.A.
        • Thiboutot D.
        IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway.
        J Invest Dermatol. 2008; 128: 1286-1293
        • Zouboulis C.C.
        • Schagen S.
        • Alestas T.
        The sebocyte culture: a model to study the pathophysiology of the sebaceous gland in sebostasis, seborrhoea and acne.
        Arch Dermatol Res. 2008; 300: 397-413
        • Bennett M.K.
        • Lopez J.M.
        • Sanchez H.B.
        • Osborne T.F.
        Sterol regulation of fatty acid synthase promoter. Coordinate feedback regulation of two major lipid pathways.
        J Biol Chem. 1995; 270: 25578-25583
        • Rao K.M.
        MAP kinase activation in macrophages.
        J Leukoc Biol. 2001; 69: 3-10
        • Kyriakis J.M.
        Activation of the AP-1 transcription factor by inflammatory cytokines of the TNF family.
        Gene Expr. 1999; 7: 217-231
        • Chang Y.
        • Wang J.
        • Lu X.
        • Thewke D.P.
        • Mason R.J.
        KGF induces lipogenic genes through a PI3K and JNK/SREBP-1 pathway in H292 cells.
        J Lipid Res. 2005; 46: 2624-2635
        • Kotzka J.
        • Muller-Wieland D.
        • Roth G.
        • Kremer L.
        • Munck M.
        • Schurmann S.
        • et al.
        Sterol regulatory element binding proteins (SREBP)-1a and SREBP-2 are linked to the MAP-kinase cascade.
        J Lipid Res. 2000; 41: 99-108
        • Campione E.
        • Mazzotta A.M.
        • Bianchi L.
        • Chimenti S.
        Severe acne successfully treated with etanercept.
        Acta Derm Venereol. 2006; 86: 256-257
        • Kang S.
        • Cho S.
        • Chung J.H.
        • Hammerberg C.
        • Fisher G.J.
        • Voorhees J.J.
        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. 2005; 166: 1691-1699
        • Bialecka A.
        • Mak M.
        • Biedron R.
        • Bobek M.
        • Kasprowicz A.
        • Marcinkiewicz J.
        Different pro-inflammatory and immunogenic potentials of Propionibacterium acnes and Staphylococcus epidermidis: implications for chronic inflammatory acne.
        Arch Immunol Ther Exp (Warsz). 2005; 53: 79-85
        • Vowels B.R.
        • Yang S.
        • Leyden J.J.
        Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne.
        Infect Immun. 1995; 63: 3158-3165
        • Chiang C.T.
        • Weng M.S.
        • Lin-Shiau S.Y.
        • Kuo K.L.
        • Tsai Y.J.
        • Lin J.K.
        Pu-erh tea supplementation suppresses fatty acid synthase expression in the rat liver through downregulating Akt and JNK signalings as demonstrated in human hepatoma HepG2 cells.
        Oncol Res. 2005; 16: 119-128
        • Engelman J.A.
        • Lisanti M.P.
        • Scherer P.E.
        Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis.
        J Biol Chem. 1998; 273: 32111-32120
        • Hao J.
        • Liu S.
        • Zhao S.
        • Liu Q.
        • Lv X.
        • Chen H.
        • et al.
        PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-beta1.
        Histochem Cell Biol. 2011; 135: 173-181
        • Moon J.S.
        • Jin W.J.
        • Kwak J.H.
        • Kim H.J.
        • Yun M.J.
        • Kim J.W.
        • et al.
        Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells.
        Biochem J. 2010; 433: 225-233
        • Kohn A.D.
        • Summers S.A.
        • Birnbaum M.J.
        • Roth R.A.
        Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation.
        J Biol Chem. 1996; 271: 31372-31378
        • Porstmann T.
        • Griffiths B.
        • Chung Y.L.
        • Delpuech O.
        • Griffiths J.R.
        • Downward J.
        • et al.
        PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.
        Oncogene. 2005; 24: 6465-6481
        • Du X.
        • Kristiana I.
        • Wong J.
        • Brown A.J.
        Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesis.
        Mol Biol Cell. 2006; 17: 2735-2745
        • Downie M.M.
        • Sanders D.A.
        • Kealey T.
        Modelling the remission of individual acne lesions in vitro.
        Br J Dermatol. 2002; 147: 869-878
        • Guy R.
        • Kealey T.
        The effects of inflammatory cytokines on the isolated human sebaceous infundibulum.
        J Invest Dermatol. 1998; 110: 410-415
        • Grunfeld C.
        • Verdier J.A.
        • Neese R.
        • Moser A.H.
        • Feingold K.R.
        Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.
        J Lipid Res. 1988; 29: 1327-1335
        • Endo M.
        • Masaki T.
        • Seike M.
        • Yoshimatsu H.
        TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c).
        Exp Biol Med (Maywood). 2007; 232: 614-621
        • Ruan H.
        • Lodish H.F.
        Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.
        Cytokine Growth Factor Rev. 2003; 14: 447-455
        • Sewter C.
        • Berger D.
        • Considine R.V.
        • Medina G.
        • Rochford J.
        • Ciaraldi T.
        • et al.
        Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha.
        Diabetes. 2002; 51: 1035-1041
        • Sladden M.J.
        • Clarke P.J.
        • Mitchell B.
        Infliximab-induced acne: report of a third case.
        Br J Dermatol. 2008; 158: 172
        • Bassi E.
        • Poli F.
        • Charachon A.
        • Claudepierre P.
        • Revuz J.
        Infliximab-induced acne: report of two cases.
        Br J Dermatol. 2007; 156: 402-403
        • Steels E.
        • Peretz A.
        • Vereecken P.
        Infliximab-induced acne: a new case and review of published reports.
        J Dermatolog Treat. 2009; 20: 59-60