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TC1(C8orf4) is upregulated by IL-1b/TNF-a and enhances proliferation of human follicular dendritic cells Youngmi Kima,1, Jungtae Kima,1, Juhee Parka, Seunghyun Banga, Yusun Junga, Jongseon Choeb, Kyuyoung Songc, Inchul Leed,* a Asan Institute for Life Sciences, University of Ulsan, College of Medicine, Seoul 138-736, Republic of Korea b Department of Microbiology and Immunology, Kangwon National University, College of Medicine, Chunchon, Kangwon-Do 200-701, c Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul 138-736, Republic of Korea d Department of Pathology, University of Ulsan, College of Medicine, 388-1 Poongnap-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea Received 29 March 2006; revised 9 May 2006; accepted 15 May 2006 that has been widely implicated in regulating cell proliferation Follicular dendritic cells (FDC) play crucial roles in in cancers and development . TC1 is a small protein in immune regulation. TNF-a has been shown to be essential tothe FDC network. However, the molecular regulation of FDC vertebrates which enhances the signaling pathway by proliferation has not been characterized. Here, we show that relieving the antagonistic function of Chibby on b-catenin TC1(C8orf4), a novel positive regulator of the Wnt/b-catenin mediated transcription TC1 enhances cancer cell prolifer- pathway in vertebrates, is upregulated by IL-1b and TNF-a in ation and invasiveness The expression of TC1 cor- the human FDC-like line HK. TC1 enhances HK cell prolifera- related with aggressive biological behavior of gastric cancer tion, while TC1-knockdown inhibits the proliferation induced by and with poor survival . However, the transcriptional reg- IL-1b, suggesting a role of TC1 as a regulator of FDC prolifer- ulation of TC1 has remained to be investigated.
ation. The regulation by pro-inflammatory cytokines suggests In this study, we investigated the biological effects of TNF-a that TC1 might be implicated in linking local inflammation to and IL-1b on TC1 expression. Human FDC-like line HK immune response by stimulating FDC.
Ó was used for the investigation because of the crucial roles of 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
FDCs in the immune system and the requirement of TNF-afor the proliferation. We were also interested in the potential Keywords: TC1(C8orf4); NF-kB; IL-1b; TNF-a; biological role of TC1 in non-neoplastic primary culture cells.
Here, we show that IL-1b and TNF-a upregulate TC1 expression in a NF-jB-dependent manner. TC1 upregulatedb-catenin target genes in HK cells as in cancer cells. TC1 en-hanced the proliferation of HK cells while TC1-knockdowninhibited the proliferation induced by IL-1b, suggesting a bio- logical role of TC1 as a major regulator of FDC proliferation.
The regulation of TC1 by pro-inflammatory cytokines suggests Follicular dendritic cells (FDC) play crucial roles in germinal that it might be implicated in linking local inflammation to B center formation and B cell differentiation (reviewed in FDCs display elaborate cytoplasmic processes which pres-ent native antigens on the surface in the form of immune-complexes through Fc receptors and complement receptors.
FDCs organize mature lymphoid follicles collaborating withB and T cells . TNF-a has been shown to be essential FDC-like cell line HK was established from human tonsils and to the development of the FDC network in germinal centers grown in RPMI 1640 supplemented with 10% fetal bovine serum, . Pro-inflammatory cytokines TNF-a and IL-1b activate 2 mM L-glutamine, and 80 lg/ml gentamicin in a humidified atmo- IKKs, which target IjB for polyubiquitination and subsequent sphere of 5% CO2 at 37 °C . Experiments were done using degradation by proteasome, thereby releasing NF-jB. The acti- HK cells of 9–13 passages. Human recombinant IL-1b and TNF-a vation of NF-jB has been widely implicated in regulation of were purchased commercially (Sigma, St. Louis, MO), and appliedat 20 U/ml media and 10 ng/ml, respectively. Sulindac sulfide and immunity, inflammation, and apoptosis . However, it has PDTC (pyrrolidine dithiocarbamate) were also purchased (Sigma), remained to be elucidated how NF-jB activation enhances Recently, we have reported that TC1(C8orf4) functions as a positive regulator of the Wnt/b-catenin signaling pathway HA-TC1 construct in pcDNA3 vector (Invitrogen, Carldbad, CA) was described previously Lenti-TC1, a full length TC1-expressinglentiviral vector was constructed by inserting TC1 ORF into lentiM1.2 *Corresponding author. Fax: +82 2 472 7898.
vector (VectorCore A Inc., Deajeon, Korea), which had mCMV pro- moter for the expression and eGFP-Zeocin fusion protein under IRESpromoter. LentiM1.4-eGFP vector was used as control. Lenti-siTC1, 1 Both authors contributed equally to this work.
a shRNA-expression lentiviral vector for targeting TC1 gene, was also 0014-5793/$32.00 Ó 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.febslet.2006.05.036 Y. Kim et al. / FEBS Letters 580 (2006) 3519–3524 constructed by inserting synthetic oligonucleotide, 50-CGGAATT- CACACAGACCAAGAATCACTAGAAAGttcaagagaCTTTCTAGTG-ATTCTTGGTCTGTGTTTTTTGATATCTAGACA-30 letters represent sense and antisense sequences of TC1, small lettersrepresent an insert for loop, and the 5 Ts represent a transcription stop signal) into the EcoRI–XbaI site of shLenti2.4G vector (VectorCore A Inc.). The siRNA sequence was previously shown to downregulateTC1 expression efficiently and specifically . The control con- sisted of scrambled shRNA sequences (50-AATCGCATAGCG-TATGCCGTT-30) inserted into the same vector. Lentiviruses were prepared according to the standard protocol 2.3. Real-time and semiquantitative RT-PCR TC1 expression levels were measured using real-time PCR analysis.
HK cells were treated with IL-1b, TNF-a, sulindac and/or PDTC as indicated. Total RNA was extracted using Trizol reagent (Invitrogen) and cDNA was synthesized using Superscript II reverse transcriptase (Invitrogen). Quantitative PCR was performed using a continuousfluorescence detecting thermal cycler ABI PRISMÒ 7000 Sequence Detection System (ABI, Foster city, CA), and a SYBRÒ Green real- time PCR master mix (Toyobo, Osaka, Japan). Measurements weredone in triplicate using b-actin gene as an endogenous control. For the statistical analysis, analysis of variance (ANOVA) test was applied using the SPSS software (SPSS Inc. Chicago, IL).
The expressions of TC1 and/or b-catenin target genes were analyzed after Lenti-TC1 or Lenti-siTC1 transfection using corresponding con- trol vectors and b-actin as loading control. Semiquantitative RT-PCR was done as described previously using primers for TC1, 50- caagccatcatcatgtccac-30 and 50-gttgcccacggctttcttac-30; c-Myc, 50-tgctc- catgaggagacacc-30 and 50-ctctgaccttttgccaggag-30; c-MET, 50-gcatttt-tacggacccaatc-30 and 50-gctgcaaagctgtggtaaac-30; Cyclin D1, 50- tcctctccaaaatgccagag-30 and 50-ggcggattggaaatgaact-30; and b-actin 50-ggcacccagcacaatgaag-30 and 50-gccgatccacacggagtact-30.
Fig. 1. (A) TC1 upregulation by IL-1b in HK cells. After the treatment of 20 U/ml IL-1b, TC1 mRNA levels were measured by SYBR-green HK cells grown on cover slips were immunostained using rabbit real-time PCR in quadruplicate using b-actin as internal control. The anti-Rel A antiserum (Santa Cruz Biotechnology, Santa Cruz, CA).
TC1 expression is enhanced in an hour, reaching more than 10 times of After washing with PBS, FITC-labeled anti-rabbit second antibody the basal level in 3 h. (B) TC1 upregulation by IL-1b and TNF-a. TC1 (Jackson Immunoresearch, West Grove, PN) was applied. DNA stain- levels were measured at 6 h after the treatment of 20 U/ml IL-1b and/ ing was done with DAPI (Sigma). Cells were viewed using an Olympus or 10 ng/ml TNF-a. TNF-a also enhances TC1 but to a lesser degree BX51 fluorescence microscope. For control, the primary antibody was than IL-1b does. IL-1b and TNF-a together show a synergistic effect.
and NF-jB inhibitor PDTC Both sulindac sulfide, an ac- The proliferation of HK cells with or without treatment of IL-1b tive metabolite of sulindac, and PDTC were applied at rela- and/or TNF-a was analyzed using WST-1 proliferation assay kit tively low levels, 50 lM, which did not affect cell growth or according to the manufacturer’s instruction (Roche, Mannheim, Ger- damage (data not shown). After 3 h, TC1 levels were measured many). Lenti-TC1 or Lenti-siTC1-transfected HK cells were analyzed and compared with untreated control. Both sulindac and using corresponding controls. Measurements were done in quadrupli-cate at 24, 48, and 72 h after cytokine treatments, and fold changes in PDTC inhibited IL-1b-induced TC1 upregulation significantly comparison with controls were analyzed using ANOVA test.
(P < 0.001), suggesting that the upregulation was NF-jB-dependent ). Given the prompt upregulation of TC1after the cytokine treatments, our data suggested TC1 as one 3.1. IL-1b and TNF-a enhances TC1 expression in HK cells 3.3. NF-kB activation by IL-1b in HK cells TC1 expression was at low level in HK cells normally. Upon It has been shown that TNF-a activates NF-jB in HK cells IL-1b treatment, TC1 expression was upregulated promptly, . However, the effect of IL-1b on the NF-jB activation has reaching more than 10 times of the basal level in 3 h as mea- not been reported in HK cells. Upon the activation by the cyto- sured by real-time PCR A). After 24 h, TC1 expression kines, NF-jB is released from IjB to be translocated into the decreased to remain at a considerably high level compared to nucleus . Then, NF-jB regulates target genes including the untreated control. Under the experimental conditions, IjB and, thereby, the transcriptional activity of NF-jB is re- IL-1b upregulated TC1 much more than TNF-a did duced again rather rapidly upon the negative feedback by en- IL-1b and TNF-a enhanced the proliferation syner- immunofluorescence staining for Rel A, a subunit of NF-jB.
Upon IL-1b treatment, the nuclear RelA immunostaining 3.2. IL-1b-induced TC1 upregulation is NF-kB-dependent was detected in 30 min, and then decreased mildly after 3 h The upregulation of TC1 by IL-1b and TNF-a suggested (). The nuclear immunostaining largely disappeared in that TC1 might be a target gene of NF-jB. To test the hypoth- 24 h. Our data showed that IL-1b also activated NF-jB in esis, we then analyzed the effects of IKK inhibitor sulindac Y. Kim et al. / FEBS Letters 580 (2006) 3519–3524 3.4. TC1 upregulates b-catenin target genes in HK cells Previously, we have shown that TC1 upregulates b-catenin target genes in cancer cells Because TC1 expression level was quite low in HK line, a gain-of-function study by introduc-ing exogenous TC1 would have been appropriate. However, HK cells are resistant to conventional gene transfer methods (data not shown). Thus, we constructed the full length TC1 in lentiviral vector to facilitate the gene transfer. HK cells were transfectedwith lentiviral constructs effectively so that most cells expressed GFP in 24 h (data not shown). TC1-transfected HK cells showed markedly upregulated TC1 expression in comparison with con- trol vector-transfected cells as measured by real-time PCR Fig. 2. Effect of sulindac and PDTC on IL-1b-induced TC1 upregu- The expressions of cyclin D1, c-Myc, and c-Met were lation. HK cells were treated with 20 U/ml IL-1b, 50 lM sulindac enhanced significantly compared to the control as sulfide, and/or 50 lM PDTC. After 3 h, TC1 levels were measured by measured by semiquantitative RT-PCR . They are b-catenin SYBR-green real-time PCR in quadruplicate using b-actin as internal target genes and are implicated in cell proliferation (reviewed in control. Sulindac and PDTC inhibited TC1 upregulation by IL-1bin a dose-dependent manner, suggesting an NF-jB-dependent ). Our data suggest that TC1 functions as a positive reg- ulator of the Wnt/b-catenin signaling pathway in HK cells also.
Fig. 3. IL-1b induces nuclear translocation of NF-jB activation by in HK cells. HK cells grown on cover slips were immunostained using rabbit anti-Rel A antiserum. After washing with PBS, FITC-labeled anti-rabbit second antibody was applied. DNA staining was done using DAPI, and cellswere viewed using Olympus BX51 fluorescence microscope.
Y. Kim et al. / FEBS Letters 580 (2006) 3519–3524 Fig. 4. TC1 upregulates b-catenin target genes in HK cells. (A) TC1 expression in Lenti-TC1 or control vector-transfected cells. The expression wasmeasured by real-time PCR in quadruplicate using b-actin as internal control. (B) Semiquantitative RT-PCR for b-catenin target genes cyclin D1, c-Myc and c-Met in Lenti-TC1-transfected HK cells and control vector-transfected cells. Densitometric values were normalized using b-actin asloading control.
We then investigated the effect of TC1 transfection with or The upregulation of cyclin D1, c-Myc, and c-Met suggested without IL-1b treatment. TC1-transfected cells showed signif- that TC1 might enhance the proliferation of HK cells. We first icant enhancement of proliferation in 72 h compared to the analyzed the effects of IL-1b and TNF-a on HK cell prolifer- control vector-transfected cells (P < 0.001, The ation. TNF-a was shown to enhance the proliferation of HK enhancement by TC1 was higher than that by IL-1b alone in cells ; however, the role of IL-1b has not been reported.
72 h (P < 0.05). TC1 and IL-1b showed an additive effect on IL-1b and TNF-a showed similar enhancing effects on the pro- liferation compared to untreated HK cells (P < 0.001, To investigate the normal requirements of TC1 in HK cell A). IL-1b and TNF-a together showed a significant syn- proliferation, we next analyzed the effect of TC1 knockdown ergistic effect (P < 0.001), enhancing the proliferation continu- on HK cell proliferation. Lenti-siRNA was constructed using a siRNA sequence that was shown to downregulate TC1 Absorbance (A
Absorbance (A
Time (hr)
Time (hr)
Expression fold 0.25
Absorbance (A 1.5
Time (hr)
Fig. 5. TC1 and cytokine effects on HK cell proliferation. (A) Effects of IL-1b and/or TNF-a on HK cell proliferation. 20 U/ml IL-1b and/or 10 ng/ml TNF-a was applied to HK cells, and the proliferation was analyzed using WST-1 proliferation assay kit (Roche). Measurements were done inquadruplicate at 24, 48, and 72 h after cytokine treatments. Fold changes were analyzed in comparison with controls using ANOVA test. (B) Theproliferation of TC1-Lenti- and control vector-transfected HK cells with or without IL-1b was measured similarly. (C) TC1 knockdown using Lenti-siTC1 transfection compared to the control vector-transfected HK cells. TC1 was measured by real-time PCR in quadruplicate using b-actin asinternal control. (D) The proliferation of Lenti-siTC1- and control vector-transfected HK cells with or without IL-1b was measured similarly.
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