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TNF-α production in the skin

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Abstract

Upregulation of TNF-α is a key early response to ultraviolet B (UVB) by keratinocytes (KCs), and represents an important component of the inflammatory cascade in skin. UVB irradiation induces TNF-α expression in both KCs and dermal fibroblasts, with TNF-α mRNA induction seen as early as 1.5 h after UVB. We previously reported that the effects are wavelength-specific: TNF-α expression and secretion are induced by UVB (290–320 nm), but not by UVA (320–400 nm). Moreover, we found that IL-1α, a cytokine also present in irradiated skin, substantially and synergistically enhances the induction of TNF-α by UVB, and the induction of TNF-α by this combination of UVB with IL-1α is mediated through increased TNF-α gene transcription. We investigated the molecular mechanism for UVB-induction of the TNF-α gene with a series of TNF-α promoter constructs, ranging from 1.2 kbp (from −1179 to +1 with respect to the TNF-α transcription initiation site) down to 0.1 kbp (−109 to +1), each driving expression of a CAT reporter. Our results showed a persistent nine to tenfold increase of CAT activity in all TNF-α promoter/reporter constructs in response to UVB (30 mJ/cm2) exposure. These results indicate the presence of UVB-responsive cis-element(s) located between −109 and +1 of the TNF-α promoter, a region that contains a putative AP-1 site and a putative NFkB site. UVB-induction was abolished when the TNF-α promoter was mutated by one base pair at the AP-1 binding site. Cells treated with SP600125, an AP-1 inhibitor that inhibits JNK (c-Jun N-terminal kinase), also showed suppression of the 0.1 kbp TNF-α promoter/reporter construct. The authentic endogenous gene in untransfected cells was also blocked by the inhibitor. Electrophoretic Mobility Shift Assay indicated new complexes from UVB-treated nuclear extracts and anti-phospho-c-Jun, a regulatory component of the AP-1 transcription factor, creating a supershift indicating increased phosphorylation of c-Jun and hence higher AP-1 activity. Keratinocyte-derived TNF-α is a component of the early induction phase of the inflammatory cascade.

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Abbreviations

KCs:

Keratinocytes

FBs:

Fibroblasts

UVB:

Ultraviolet B

TNF-α:

Tumor necrosis factor-α

References

  1. Abraham LJ, Kroeger KM (1999) Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol 66:562–566

    PubMed  CAS  Google Scholar 

  2. Adachi M, Gazel A, Pintucci G, Shuck A, Shifteh S, Ginsburg D et al (2003) Specificity in stress response: epidermal keratinocytes exhibit specialized UV-responsive signal transduction pathways. DNA Cell Biol 22:665–677. doi:10.1089/104454903770238148

    Article  PubMed  CAS  Google Scholar 

  3. Barkauskaite V, EK M, Popovic K, Harris HE, Wahren-Herlenius M, Nyberg F (2007) Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus. Lupus 10:794–802. doi:10.1177/0961203307081895

    Article  Google Scholar 

  4. Bashir MM, Sharma M, Werth VP (2006) UVB-induction of TNF-α gene transcription requires a response element, overlapping the AP-1-binding site, of the proximal promoter. J Invest Dermatol 126:277. doi:10.1038/sj.jid.5700067

    Article  Google Scholar 

  5. Bashir M, Sharma M, Werth VP (2007) Mechanism of induction of TNF-α in response to UVB and IL-1α. J Invest Dermatol 127:S139

    Google Scholar 

  6. Bazzoni F, Kruys V, Shakhov A, Jongeneel CV, Beutler B (1994) Analysis of tumor necrosis factor promoter responses to ultraviolet light. J Clin Invest 93:56–62. doi:10.1172/JCI116984

    Article  PubMed  CAS  Google Scholar 

  7. Briscoe DM, Cotran RS, Pober JS (1992) Effects of tumor necrosis factor, lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule-1 in vivo. Correlation with CD3 + T cell infiltration. J Immunol 149:2954–2960

    PubMed  CAS  Google Scholar 

  8. Clingen PH, Berneburg M, Petit-Frere C, Woollons A, Lowe JE, Arlett CF et al (2001) Contrasting effects of an ultraviolet B and an ultraviolet A tanning lamp on interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1 expression. Br J Dermatol 145:54–62. doi:10.1046/j.1365-2133.2001.04281.x

    Article  PubMed  CAS  Google Scholar 

  9. de Kossodo S, Cruz PD Jr, Dougherty I, Thompson P, Silva-Valdez M (1995) Expression of the tumor necrosis factor gene by dermal fibroblasts in response to ultraviolet irradiation or lipopolysaccharide. J Invest Dermatol 104:318–322. doi:10.1111/1523-1747.ep12665361

    Article  PubMed  Google Scholar 

  10. Fisher GJ, Datta SC, Talwar HS, Wang Z-Q, Varani J, Kang S et al (1996) Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379:335–339. doi:10.1038/379335a0

    Article  PubMed  CAS  Google Scholar 

  11. Fujisawa H, Wang B, Kondo S, Shivji GM, Sauder DN (1997) Costimulation with ultraviolet B and interleukin-1 alpha dramatically increase tumor necrosis factor-alpha production in human dermal fibroblasts. J Interferon Cytokine Res 17:307–313

    PubMed  CAS  Google Scholar 

  12. Kashiwa H, Wright SC, Bonavida B (1987) Regulation of B cell maturation and differentiation. I. Suppression of pokeweed mitogen-induced B cell differentiation by tumor necrosis factor (TNF). J Immunol 138:1383–1390

    PubMed  CAS  Google Scholar 

  13. Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. J Mol Med 83:97–109. doi:10.1007/s00109-004-0603-7

    Article  PubMed  CAS  Google Scholar 

  14. Kock A, Schwarz T, Kirnbauer R, Urbanski A, Perry P, Ansel JC et al (1990) Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 172:1609–1614. doi:10.1084/jem.172.6.1609

    Article  PubMed  CAS  Google Scholar 

  15. Kroeger KM, Carville KS, Abraham LJ (1997) The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 34:391–399. doi:10.1016/S0161-5890(97)00052-7

    Article  PubMed  CAS  Google Scholar 

  16. Kroeger KM, Steer JH, Joyce DA, Abraham LJ (2000) Effects of stimulus and cell type on the expression of the -308 tumour necrosis factor promoter polymorphism. Cytokine 12:110–119. doi:10.1006/cyto.1999.0529

    Article  PubMed  CAS  Google Scholar 

  17. Krutmann J, Kock A, Schauer E, Parlow F, Moller A, Kapp A et al (1990) Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression. J Invest Dermatol 95:127–131. doi:10.1111/1523-1747.ep12477839

    Article  PubMed  CAS  Google Scholar 

  18. Lisby S, Hauser C (2002) Transcriptional regulation of tumor necrosis factor-alpha in keratinocytes mediated by interleukin-1beta and tumor necrosis factor-alpha. Exp Dermatol 11:592–598. doi:10.1034/j.1600-0625.2002.110612.x

    Article  PubMed  CAS  Google Scholar 

  19. Liu H, Sidiropoulos P, Song G, Pagliari LJ, Birrer MJ, Stein B et al (2000) TNF-alpha gene expression in macrophages: regulation by NF-kappa B is independent of c-Jun or C/EBP beta. J Immunol 164:4277–4285

    PubMed  CAS  Google Scholar 

  20. Matsuura K, Otsuka F, Fujisawa H (1998) Effects of interferons on tumour necrosis factor alpha production from human keratinocytes. Cytokine 10:500–505. doi:10.1006/cyto.1997.0326

    Article  PubMed  CAS  Google Scholar 

  21. Meller S, Winterberg F et al (2005) Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum 52:1504–1516. doi:10.1002/art.21034

    Article  PubMed  CAS  Google Scholar 

  22. Millard TP, Kondeatis E, Cox A, Wilson AG, Grabczynska SA, Carey BS et al (2001) A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo. Br J Dermatol 145:229–236. doi:10.1046/j.1365-2133.2001.04339.x

    Article  PubMed  CAS  Google Scholar 

  23. Niizeki H, Inoki H, Streilein JW (2002) Polymorphisms in the TNF region confer susceptibiilty to UVB-induced impairment of contact hypersensitivity induction in mice and humans. Methods 28:46–54. doi:10.1016/S1046-2023(02)00211-6

    Article  PubMed  CAS  Google Scholar 

  24. Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez EP, Kinder JM et al (2000) TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum 43:2368–2377. doi:10.1002/1529-0131(200010)43:10<2368::AID-ANR26>3.0.CO;2-8

    Article  PubMed  CAS  Google Scholar 

  25. Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J (2005) Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 102:3372–3377. doi:10.1073/pnas.0408506102

    Article  PubMed  CAS  Google Scholar 

  26. Popovic K, EK M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, Nyberg F (2005) Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erthematosus. Arthritis Rheum 52:3639–3645. doi:10.1002/art.21398

    Article  PubMed  CAS  Google Scholar 

  27. Schwarz A, Bhardwaj R, Aragane Y, Mahnke K, Riemann H, Metze D et al (1995) Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells. J Invest Dermatol 104:922–927. doi:10.1111/1523-1747.ep12606202

    Article  PubMed  CAS  Google Scholar 

  28. Solt LA, Madge LA, Orange JS, May MJ (2007) Interleukin-1-induced NF-κB activation is NEMO-dependent but does not require IKKbeta. JBC 282:8724–8733

    Google Scholar 

  29. Suschek CV, Mahotka C, Schnorr O, Kolb-Bachofen V (2004) UVB radiation-mediated expression of inducible nitric oxide synthase activity and the augmenting role of co-induced TNF-alpha in human skin endothelial cells. J Invest Dermatol 123:950–957. doi:10.1111/j.0022-202X.2004.23422.x

    Article  PubMed  CAS  Google Scholar 

  30. Swerlick RA, Lee KH, Li KLJ, Sepp NT, Caughman SW, Lawley TJ (1992) Regulation of vascular cell adhesion molecule 1 on human dermal microvascular endothelial cells. J Immunol 149:698–705

    PubMed  CAS  Google Scholar 

  31. Tanos T, Marinessen MJ, Leskow FC, Hochbaum D, Martinetto H, Gutkind JS et al (2005) Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light. J Biol Chem 280:18842–18852. doi:10.1074/jbc.M500620200

    Article  PubMed  CAS  Google Scholar 

  32. Wan YS, Wang ZQ, Voorhees J, Fisher G (2001) EGF receptor crosstalks with cytokine receptors leading to activation of c-Jun kinase in response to UV irradiation in human keratinocytes. Cell Signal 13:139–144. doi:10.1016/S0898-6568(00)00146-7

    Article  PubMed  CAS  Google Scholar 

  33. Werth VP, Zhang W (1999) Wavelength-specific synergy between ultraviolet radiation and interleukin-1 alpha in the regulation of matrix-related genes: mechanistic role for tumor necrosis factor-alpha. J Invest Dermatol 113:196–201. doi:10.1046/j.1523-1747.1999.00681.x

    Article  PubMed  CAS  Google Scholar 

  34. Werth VP, Zhang W, Dortzbach K, Sullivan K (2000) Association of a promoter polymorphism of TNFalpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol 115:726–730. doi:10.1046/j.1523-1747.2000.00118.x

    Article  PubMed  CAS  Google Scholar 

  35. Yarosh D, Both D, Kibitel J, Anderson C, Elmets C, Brash D et al (2000) Regulation of TNFalpha production and release in human and mouse keratinocytes and mouse skin after UV-B radiation. Photodermatol Photoimmunol Photomed 16:263–270. doi:10.1034/j.1600-0781.2000.160606.x

    Article  PubMed  CAS  Google Scholar 

  36. Zhuang L, Wang B, Shinder GA, Shivji GM, Mak TW, Sauder DN (1999) TNF receptor p55 plays a pivotal role in murine keratinocyte apoptosis induced by ultraviolet B irradiation. J Immunol 162:1440–1447

    PubMed  CAS  Google Scholar 

  37. Zhuang L, Wang B, Sauder DN (2000) Molecular mechanism of ultraviolet-induced keratinocyte apoptosis. J Interferon Cytokine Res 20:445–454. doi:10.1089/10799900050023852

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The work is supported by a V.A. Merit Review Grant (V.P.W).

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The authors have no potential conflict of interest.

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Correspondence to V. P. Werth.

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Bashir, M.M., Sharma, M.R. & Werth, V.P. TNF-α production in the skin. Arch Dermatol Res 301, 87–91 (2009). https://doi.org/10.1007/s00403-008-0893-7

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