TAK1 Is a Master Regulator of Epidermal Homeostasis Involving Skin Inflammation and Apoptosis
Transforming growth factor β-activated kinase 1 (TAK1) functions downstream of inflammatory cytokines to activate c-Jun N-terminal kinase (JNK) as well as NF-κB in several cell types. However, the functional role of TAK1 in an in vivo setting has not been determined. Here we have demonstrated that TAK1 is the major regulator of skin inflammation as well as keratinocyte death in vivo. Epidermal-specific deletion of TAK1 causes a severe inflammatory skin condition by postnatal day 6-8. The mutant skin also exhibits massive keratinocyte death. Analysis of keratinocytes isolated from the mutant skin revealed that TAK1 deficiency results in a striking increase in apoptosis in response to tumor necrosis factor (TNF). TAK1-deficient keratinocytes cannot activate NF-κB or JNK upon TNF treatment. These results suggest that TNF induces TAK1-deficient keratinocyte death because of the lack of NF-κB (and possibly JNK)-mediated cell survival signaling. Finally, we have shown that deletion of the TNF receptor can largely rescue keratinocyte death as well as inflammatory skin condition in epidermal-specific TAK1-deficient mice. Our results demonstrate that TAK1 is a master regulator of TNF signaling in skin and regulates skin inflammation and keratinocyte death. Transforming growth factor β-activated kinase 1 (TAK1) functions downstream of inflammatory cytokines to activate c-Jun N-terminal kinase (JNK) as well as NF-κB in several cell types. However, the functional role of TAK1 in an in vivo setting has not been determined. Here we have demonstrated that TAK1 is the major regulator of skin inflammation as well as keratinocyte death in vivo. Epidermal-specific deletion of TAK1 causes a severe inflammatory skin condition by postnatal day 6-8. The mutant skin also exhibits massive keratinocyte death. Analysis of keratinocytes isolated from the mutant skin revealed that TAK1 deficiency results in a striking increase in apoptosis in response to tumor necrosis factor (TNF). TAK1-deficient keratinocytes cannot activate NF-κB or JNK upon TNF treatment. These results suggest that TNF induces TAK1-deficient keratinocyte death because of the lack of NF-κB (and possibly JNK)-mediated cell survival signaling. Finally, we have shown that deletion of the TNF receptor can largely rescue keratinocyte death as well as inflammatory skin condition in epidermal-specific TAK1-deficient mice. Our results demonstrate that TAK1 is a master regulator of TNF signaling in skin and regulates skin inflammation and keratinocyte death. TAK1 2The abbreviations used are: TAK1, TGF-β-activated kinase 1; TGF, transforming growth factor; IL-1, interleukin 1; TNF, tumor necrosis factor; JNK, c-Jun N-terminal kinase; IKK, IκB kinase; K5, 6, 10, and 16, keratins 5, 6, 10, and 16; TUNEL, terminal dUTP nick-end labeling. (transforming growth factor β-activated kinase 1) is a member of the mitogen-activated protein kinase kinase kinase family and is activated by inflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) and Toll-like receptor ligands (1Akira S. Takeda K. Nat. Rev. Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6751) Google Scholar, 2Ninomiya-Tsuji J. Kishimoto K. Hiyama A. Inoue J. Cao Z. Matsumoto K. Nature. 1999; 398: 252-256Crossref PubMed Scopus (1023) Google Scholar). In IL-1, TNF, and Toll-like receptor ligand signaling pathways, TAK1 has been shown to be an essential signaling intermediate that functions upstream of IκB kinase (IKK)-NF-κB and c-Jun N-terminal kinase (JNK) in B cells and some culture cells (3Sato S. Sanjo H. Takeda K. Ninomiya-Tsuji J. Yamamoto M. Kawai T. Matsumoto K. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 1087-1095Crossref PubMed Scopus (767) Google Scholar, 4Shim J.H. Xiao C. Paschal A.E. Bailey S.T. Rao P. Hayden M.S. Lee K.Y. Bussey C. Steckel M. Tanaka N. Yamada G. Akira S. Matsumoto K. Ghosh S. Genes Dev. 2005; 19: 2668-2681Crossref PubMed Scopus (597) Google Scholar, 5Takaesu G. Surabhi R.M. Park K.J. Ninomiya-Tsuji J. Matsumoto K. Gaynor R.B. J. Mol. Biol. 2003; 326: 105-115Crossref PubMed Scopus (322) Google Scholar). However, the role of TAK1 has not been established in an in vivo context due to embryonic death of TAK1 germ line knock out (3Sato S. Sanjo H. Takeda K. Ninomiya-Tsuji J. Yamamoto M. Kawai T. Matsumoto K. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 1087-1095Crossref PubMed Scopus (767) Google Scholar, 4Shim J.H. Xiao C. Paschal A.E. Bailey S.T. Rao P. Hayden M.S. Lee K.Y. Bussey C. Steckel M. Tanaka N. Yamada G. Akira S. Matsumoto K. Ghosh S. Genes Dev. 2005; 19: 2668-2681Crossref PubMed Scopus (597) Google Scholar). Skin homeostasis is maintained through a well balanced interplay of cytokines and growth factors (6Fuchs E. Raghavan S. Nat. Rev. Genet. 2002; 3: 199-209Crossref PubMed Scopus (584) Google Scholar). Several cytokines, including TNF, activate JNK and NF-κB pathways (7Ghosh S. Karin M. Cell. 2002; 109: S81-S96Abstract Full Text Full Text PDF PubMed Scopus (3300) Google Scholar, 8Varfolomeev E.E. Ashkenazi A. Cell. 2004; 116: 491-497Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar) that play critical roles in epidermal homeostasis involving skin inflammation and cancer development (9Makris C. Godfrey V.L. Krahn-Senftleben G. Takahashi T. Roberts J.L. Schwarz T. Feng L. Johnson R.S. Karin M. Mol. Cell. 2000; 5: 969-979Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 10Schmidt-Supprian M. Bloch W. Courtois G. Addicks K. Israel A. Rajewsky K. Pasparakis M. Mol. Cell. 2000; 5: 981-992Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 11Pasparakis M. Courtois G. Hafner M. Schmidt-Supprian M. Nenci A. Toksoy A. Krampert M. Goebeler M. Gillitzer R. Israel A. Krieg T. Rajewsky K. Haase I. Nature. 2002; 417: 861-866Crossref PubMed Scopus (404) Google Scholar, 12Lind M.H. Rozell B. Wallin R.P. van Hogerlinden M. Ljunggren H.G. Toftgard R. Sur I. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4972-4977Crossref PubMed Scopus (91) Google Scholar, 13van Hogerlinden M. Rozell B.L. Toftgard R. Sundberg J.P. J. Investig. Dermatol. 2004; 123: 101-108Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 14Zhang J.Y. Tao S. Kimmel R. Khavari P.A. J. Cell Biol. 2005; 168: 561-566Crossref PubMed Scopus (52) Google Scholar, 15Zhang J.Y. Green C.L. Tao S. Khavari P.A. Genes Dev. 2004; 18: 17-22Crossref PubMed Scopus (117) Google Scholar, 16Nenci A. Huth M. Funteh A. Schmidt-Supprian M. Bloch W. Metzger D. Chambon P. Rajewsky K. Krieg T. Haase I. Pasparakis M. Hum. Mol. Genet. 2006; 15: 531-542Crossref PubMed Scopus (90) Google Scholar). Inactivation of IKKβ or IKKγ, which blocks the so-called canonical NF-κB pathway, produces a severe inflammatory skin condition. Furthermore, NF-κB hypofunction is implicated in epidermal squamous cell carcinoma. In contrast, activation of JNK pathway is involved in epidermal hyperplasia and subsequent cancer development (14Zhang J.Y. Tao S. Kimmel R. Khavari P.A. J. Cell Biol. 2005; 168: 561-566Crossref PubMed Scopus (52) Google Scholar, 15Zhang J.Y. Green C.L. Tao S. Khavari P.A. Genes Dev. 2004; 18: 17-22Crossref PubMed Scopus (117) Google Scholar). Roles of IKK-NF-κB and JNK in skin have been demonstrated by using genetic and pharmacological inhibitory approaches (12Lind M.H. Rozell B. Wallin R.P. van Hogerlinden M. Ljunggren H.G. Toftgard R. Sur I. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4972-4977Crossref PubMed Scopus (91) Google Scholar, 14Zhang J.Y. Tao S. Kimmel R. Khavari P.A. J. Cell Biol. 2005; 168: 561-566Crossref PubMed Scopus (52) Google Scholar, 15Zhang J.Y. Green C.L. Tao S. Khavari P.A. Genes Dev. 2004; 18: 17-22Crossref PubMed Scopus (117) Google Scholar). However, the upstream regulators of NF-κB and JNK pathways in skin have not yet been determined. In this study, we generated and characterized mice with epidermal-specific deletion of TAK1. We found that TAK1 is an essential intermediate in TNF signaling to activate both IKK and JNK in keratinocytes. TAK1 deficiency causes severe dysregulation of skin homeostasis. Our results suggest that the dysregulation in TAK1 mutant skin is mediated by TNF-induced keratinocyte death. Mutant Mice—To generate K5CreTAK1FL/FL mice, mice carrying a floxed Map3k7 allele (TAK1FL/FL) (mixed background of C57BL/6 and 129/SvJ) (3Sato S. Sanjo H. Takeda K. Ninomiya-Tsuji J. Yamamoto M. Kawai T. Matsumoto K. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 1087-1095Crossref PubMed Scopus (767) Google Scholar) were crossed to transgenic mice expressing the Cre recombinase under the control of the keratinocyte-specific keratin 5 promoter (K5Cre) (mixed background of C57LBL/6 and DBA/2J) (17Ramirez A. Page A. Gandarillas A. Zanet J. Pibre S. Vidal M. Tusell L. Genesca A. Whitaker D.A. Melton D.W. Jorcano J.L. Genesis. 2004; 39: 52-57Crossref PubMed Scopus (165) Google Scholar). TNFR1-deficient mice C57BL/6 Tnfrsf1atm1Mak (TNFR1-/-) (18Pfeffer K. Matsuyama T. Kundig T.M. Wakeham A. Kishihara K. Shahinian A. Wiegmann K. Ohashi P.S. Kronke M. Mak T.W. Cell. 1993; 73: 457-467Abstract Full Text PDF PubMed Scopus (1541) Google Scholar) were obtained from The Jackson Laboratory. Histology and Immunohistochemistry—Sections were stained with hematoxylin and eosin for histological analysis. Immunohistochemical analysis was performed on paraffin. Bound antibodies were visualized by diaminobenzidine, and sections were counterstained with hematoxylin. dUTP nick-end labeling (TUNEL) assay was performed on paraffin sections using an apoptotic cell death detection kit (Promega) according to the manufacturer's instructions. Polyclonal antibody against TAK1 described previously (2Ninomiya-Tsuji J. Kishimoto K. Hiyama A. Inoue J. Cao Z. Matsumoto K. Nature. 1999; 398: 252-256Crossref PubMed Scopus (1023) Google Scholar), polyclonal antibodies against K5, K6, K10, loricrin, involucrin, filaggrin (Convance), IκB-α, JNK1 (FL) (Santa Cruz), caspase 3 (Cell Signaling), and phospho-JNK (Thr-183/Tyr-185) (Cell Signaling) or monoclonal antibody against β-actin (Sigma) were used. Immunofluorescence was performed on frozen sections using polyclonal antibody against TAK1 along with monoclonal antibody against nidogen (Chemicon). Bound antibodies were visualized by Cy2- or Cy3-conjugated secondary antibodies. Cell Culture—Primary and spontaneously immortalized keratinocytes derived from the skin of P0-2 mice were cultured in Ca2+-free Eagle's minimal essential medium (BioWhittaker) supplemented with 4% Chelex-treated bovine growth serum, 10 ng/ml of human epidermal growth factor (Invitrogen), 0.05 mm calcium chloride, and 1% penicillin-streptomycin at 33 °C in 8% CO2. Murine primary fibroblasts derived from the dermis of P0-2 mice were cultured in Dulbecco's modified Eagle's medium supplemented with 10% bovine growth serum at 37 °C in 5% CO2. Cytotoxicity Assays—Keratinocytes were treated with recombinant human TNF-α, mouse IL-1β, human transforming growth factor β1 (TGF-β1) (Roche Diagnostics), or lipopolysaccharide (Sigma) for 24 h. The viable adherent cells were stained with 0.1% crystal violet. The stain was solubilized by adding 50% ethanol containing 0.1 m sodium citrate, and the absorbance of each plate was determined at 595 nm. Real-time PCR Analysis—Total RNA was prepared from skin or culture keratinocytes using the RNeasy protect mini-kit (Qiagen). cDNA was synthesized using TaqMan reverse transcription reagents (Applied Biosystems). Real-time PCR analysis was performed using the ABI PRISM 7000 sequence detection system. An Assays-on-Demand gene expression kit (Applied Biosystems) was used. All samples were normalized to the signal generated from glyceraldehyde-3-phosphate dehydrogenase (GAPDH). TAK1 is expressed in both the dermis and epidermis (Fig. 1a). To investigate the role of TAK1 in epidermis in vivo,we have generated and characterized mice carrying an epidermal-specific deletion of TAK1. The mice were generated by crossing TAK1 floxed mice (TAK1FL/FL) (3Sato S. Sanjo H. Takeda K. Ninomiya-Tsuji J. Yamamoto M. Kawai T. Matsumoto K. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 1087-1095Crossref PubMed Scopus (767) Google Scholar) with a mouse line expressing Cre under the control of the epidermal-specific keratin 5 (K5) promoter (K5Cre transgenic mice) (17Ramirez A. Page A. Gandarillas A. Zanet J. Pibre S. Vidal M. Tusell L. Genesca A. Whitaker D.A. Melton D.W. Jorcano J.L. Genesis. 2004; 39: 52-57Crossref PubMed Scopus (165) Google Scholar). In this system, Cre deletes exon 2 (amino acids 41-77) of mouse TAK1, which contains an ATP binding site, and a truncated/kinase-dead version of TAK1 (TAK1Δ) is generated in K5-expressing cells, while wild-type TAK1 is expressed in other cell types. TAK1Δ was expressed in keratinocytes isolated from K5CreTAK1FL/FL mice, whereas wild-type TAK1 was detected in dermal fibroblasts from the same mice, indicating that TAK1 is specifically deleted in epidermis (Fig. 1b). K5CreTAK1FL/FL mice were born at the expected Mendelian ratios and were grossly indistinguishable from control genotype littermates from birth until postnatal day 2-3 (P2-3) (Fig. 2a). However, by P7, the K5CreTAK1FL/FL mice showed a strong cutaneous phenotype characterized by hard, inflexible skin and widespread scaling (Fig. 2a). The K5CreTAK1FL/FL mice died between P7 and P8. The control TAK1FL/FL mice as well as mice with epidermal-specific heterozygous deletion of TAK1 (K5CreTAK1FL/+) did not show any pathological phenotype. Histological analysis of skin of mice from P0, P1, P3, and P7 revealed a progressive epidermal condition involving severe apoptosis, hyperkeratosis, inflammation, and eventually epidermal erosion in K5CreTAK1FL/FL mice (Fig. 2b and Table 1). Mutant epidermis at P0 resembled normal P0 epidermis; however, by P1 numerous keratinocytes with dark pyknotic nuclei, eosinophilic cytoplasm, and absence of cellular contacts were present in the mutant epidermis (Fig. 2b, arrow). This staining pattern and cellular morphology is indicative of apoptotic keratinocytes. On P3 there were many more apoptotic basal and suprabasal keratinocytes, and hyperkeratosis was prominent. The mutant epidermis appeared highly disorganized because of keratinocyte hypertrophy, keratinocyte depletion due to apoptosis, and the presence of immune cells in intraepidermal microabscesses as well as occasional sebocytes in the epidermis (Fig. 2b, bottom panel). On P7 the epidermis was hyperplastic, hypertrophic, and severely hyperkeratotic, and areas of complete epidermal erosion accompanied by severe inflammation were common. Immune cells infiltrated into the epidermis and were found in intraepidermal microabscesses as well as embedded in the thickened hyperkeratotic stratum corneum. Sebocytes were also present in the epidermis (Fig. 2b, right column). This inflammatory condition is somehow similar to skin with epidermal-specific deletion of IKKβ or IKKγ (11Pasparakis M. Courtois G. Hafner M. Schmidt-Supprian M. Nenci A. Toksoy A. Krampert M. Goebeler M. Gillitzer R. Israel A. Krieg T. Rajewsky K. Haase I. Nature. 2002; 417: 861-866Crossref PubMed Scopus (404) Google Scholar, 16Nenci A. Huth M. Funteh A. Schmidt-Supprian M. Bloch W. Metzger D. Chambon P. Rajewsky K. Krieg T. Haase I. Pasparakis M. Hum. Mol. Genet. 2006; 15: 531-542Crossref PubMed Scopus (90) Google Scholar). However, this pronounced apoptotic phenotype has not been reported either in mutant skin with deletion of IKKβ or IKKγ (11Pasparakis M. Courtois G. Hafner M. Schmidt-Supprian M. Nenci A. Toksoy A. Krampert M. Goebeler M. Gillitzer R. Israel A. Krieg T. Rajewsky K. Haase I. Nature. 2002; 417: 861-866Crossref PubMed Scopus (404) Google Scholar, 16Nenci A. Huth M. Funteh A. Schmidt-Supprian M. Bloch W. Metzger D. Chambon P. Rajewsky K. Krieg T. Haase I. Pasparakis M. Hum. Mol. Genet. 2006; 15: 531-542Crossref PubMed Scopus (90) Google Scholar) or with inactivation of NF-κB (13van Hogerlinden M. Rozell B.L. Toftgard R. Sundberg J.P. J. Investig. Dermatol. 2004; 123: 101-108Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 14Zhang J.Y. Tao S. Kimmel R. Khavari P.A. J. Cell Biol. 2005; 168: 561-566Crossref PubMed Scopus (52) Google Scholar).TABLE 1Epidermis thickness and nucleated cell layersCTMTEpidermis thickness (μm)19 ± 5.650 ± 11.3Number of nucleated cell layers1.75 ± 0.465.33 ± 1.50 Open table in a new tab To further characterize the phenotypes of epidermal TAK1 deletion, we conducted histological and molecular analyses of mutant skin at several time points after birth. We the expression of epidermal and (Fig. These were expressed with a normal at P0 at P3, the mutant mice showed from control littermates (Fig. expression of the keratinocyte and was indicating that the keratinocyte was of keratins indicative of normal the keratin was highly in mutant skin at P3 (Fig. panel). This of that in or skin with inflammatory in which the normal of keratins with We also conducted a gene expression using and RNA isolated from K5CreTAK1FL/FL mutant and control epidermis Table The expression of many and cytokines was in the epidermal-specific TAK1 deletion mice. mice the of and We the expression of several cytokines and by We found that IL-1, inflammatory in and keratin of were highly in mutant skin at P3 (Fig. These results suggest that by P3 the epidermal TAK1 deletion produces a phenotype in the epidermis that is similar to Our histological analysis an of apoptotic keratinocytes in mutant epidermis (Fig. we apoptosis by staining and staining of activated caspase 3 (Fig. and bottom demonstrated the presence of massive of apoptotic keratinocytes in the mutant epidermis at P3 and These results demonstrate that TAK1 is essential for skin homeostasis and is involved in both inflammation and keratinocyte To to the molecular that this we keratinocytes isolated from K5CreTAK1FL/FL and TAK1FL/FL mice. We that the mutant phenotype be by a keratinocyte We found that TAK1-deficient keratinocytes at a the control keratinocytes (Fig. and were to as demonstrated by expression of and filaggrin (Fig. These results demonstrate that TAK1 is not essential for keratinocyte or that the phenotype of K5CreTAK1FL/FL is not due to a in or of TAK1-deficient keratinocytes. of IL-1, or was not in TAK1-deficient keratinocytes (Fig. This that the of gene in mutant skin (Fig. in other cell or in TAK1-deficient keratinocytes activated by from other cell types. IL-1, or is not by TAK1 We TNF and signaling pathways in TAK1-deficient keratinocytes. In wild-type keratinocytes, TNF and the activation of JNK and of However, in TAK1-deficient keratinocytes, and activation of JNK and of IκB was largely (Fig. which is similar to that in TAK1-deficient mouse embryonic fibroblasts (3Sato S. Sanjo H. Takeda K. Ninomiya-Tsuji J. Yamamoto M. Kawai T. Matsumoto K. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 1087-1095Crossref PubMed Scopus (767) Google Scholar, 4Shim J.H. Xiao C. Paschal A.E. Bailey S.T. Rao P. Hayden M.S. Lee K.Y. Bussey C. Steckel M. Tanaka N. Yamada G. Akira S. Matsumoto K. Ghosh S. Genes Dev. 2005; 19: 2668-2681Crossref PubMed Scopus (597) Google Scholar). we massive apoptosis in TAK1-deficient epidermis (Fig. we apoptosis in mutant and control keratinocytes in TAK1 an role in TNF, IL-1, and Toll-like receptor signaling pathways, of which have been reported to cell death in some cell Nat. Rev. Immunol. 2003; 3: PubMed Scopus Google Scholar, E. P. J. 1999; PubMed Scopus Google Scholar, K. G. J. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Nat. Rev. Immunol. 2005; 5: PubMed Scopus Google Scholar). we cell with TNF, IL-1, and lipopolysaccharide (Fig. We that TNF cell death in TAK1-deficient keratinocytes, whereas control keratinocytes were TNF activated caspase 3 in TAK1-deficient not in control keratinocytes (Fig. TNF was expressed in wild-type as well as mutant and the of expression were similar in both skin samples These results to that TAK1-deficient keratinocytes by of TNF expressed under normal skin which the epidermal phenotype by TAK1 To the that TNF-induced cell death is the of the phenotype of TAK1-deficient we generated of the TNF receptor (18Pfeffer K. Matsuyama T. Kundig T.M. Wakeham A. Kishihara K. Shahinian A. Wiegmann K. Ohashi P.S. Kronke M. Mak T.W. Cell. 1993; 73: 457-467Abstract Full Text PDF PubMed Scopus (1541) Google Scholar) and K5CreTAK1FL/FL The mice with the and did not severe skin (Fig. 5, a and apoptotic keratinocytes were not detected a in the skin (Fig. of IL-1, and was also detected in of the skin samples from the mice (Fig. These results demonstrate that TNF is a major of inflammatory skin in TAK1-deficient However, some mice several (Fig. Histological analysis revealed that the skin was normal for (Fig. 5, and The in some mice showed the same dysregulation as that in epidermal-specific TAK1 at (Fig. 5, and of IL-1, and was in mice at (Fig. TNF family cytokines as ligand be involved in this The and expression of inflammation and the mice were grossly normal by (Fig. 5, a and we that TNF causes cell death in TAK1-deficient keratinocytes, which in inflammatory TNF at some in the cell death is in TAK1-deficient epidermis; this causes the activation of inflammatory which results in a skin condition similar to inflammatory In this study, we found that mice carrying epidermal-specific deletion of TAK1 gene severe skin inflammation, and we to the of this phenotype. We have demonstrated that TAK1-deficient keratinocytes normal in and TAK1 deficiency causes activation of NF-κB and JNK in response to TNF induces apoptosis in TAK1-deficient keratinocytes, whereas wild-type keratinocytes to TNF Finally, we found that deletion of TNF signaling the skin phenotype of TAK1 we that TNF-induced cell death due to the lack of pathways is the of skin inflammation in TAK1 deletion mice. The of TAK1 deletion on to TNF-induced cell death is of IKKγ and IKKβ D. Wakeham A. B. D. J. Mak T.W. Genes Dev. 2000; Google Scholar, M. K. M.H. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Lee 1999; PubMed Scopus Google Scholar). the deletion of TAK1 keratinocytes to is in or in skin in vivo or in TAK1-deficient keratinocytes not is upon TNF TAK1 signaling pathways in to the NF-κB In TAK1-deficient keratinocytes, and activation of JNK is the JNK pathway has been implicated in signaling through several as of family E.E. Ashkenazi A. Cell. 2004; 116: 491-497Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar), has also been demonstrated that lack of JNK pathway protein expression and to TNF P. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The lack of both the NF-κB and JNK pathways in TAK1-deficient keratinocytes to to TNF-induced cell death. Our results demonstrate that TAK1 is the major of TNF signaling in epidermis the canonical well as JNK pathways and that TAK1 deletion TNF-induced keratinocyte death. TNF can apoptosis in many cell through caspase however, NF-κB (and possibly pathway this TNF Nat. Rev. Immunol. 2003; 3: PubMed Scopus Google Scholar). Furthermore, TNF is to to tumor development and in including skin cancer 2004; PubMed Scopus Google Scholar, G. C. N. H. L. B. Pasparakis M. G. Nat. 1999; 5: PubMed Scopus Google Scholar). of activated by the NF-κB and JNK pathways, as cytokines, and is to tumor development and TAK1 is essential for both NF-κB and JNK pathways, not TNF-induced caspase of TAK1 the of TNF and cell death. In has been demonstrated that of the NF-κB pathway in keratinocytes can increase keratinocyte apoptosis also results in the development of skin cancer (12Lind M.H. Rozell B. Wallin R.P. van Hogerlinden M. Ljunggren H.G. Toftgard R. Sur I. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4972-4977Crossref PubMed Scopus (91) Google Scholar, 15Zhang J.Y. Green C.L. Tao S. Khavari P.A. Genes Dev. 2004; 18: 17-22Crossref PubMed Scopus (117) Google Scholar). This tumor development is by deletion of or of JNK, which that TNF-induced JNK activation in the absence of NF-κB pathway skin Our results demonstrate that of TAK1 both the NF-κB and JNK pathways and suggest that TAK1 be an to skin We S. M. S. H. T. R. C. M. and K. for and with