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Cutting Edge: Roles of Caspase-8 and Caspase-10 in Innate Immune Responses to Double-Stranded RNA

Ken Takahashi^*,, Taro Kawai, Himanshu Kumar^*, Shintaro Sato, Shin Yonehara and Shizuo Akira^1,*,

^* Department of Host Defense and Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and Department of Gastroenterology and Hepatology, Graduate School of Medicine and Graduate School of Biostudies, Kyoto University, Kyoto, Japan

	Abstract

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Upon viral infection, host cells trigger antiviral immune responses by inducing type I IFN and inflammatory cytokines. dsRNA generated during viral replication is recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, which interact with an adaptor, IFN- promoter stimulator-1, to activate the transcription factors NF-B and IFN regulatory factor 3. In this article we demonstrate that caspase-8 and caspase-10 are involved in these pathways. Both caspases were cleaved during dsRNA stimulation, and overexpression of a cleaved form of these caspases activated NF-B. Knockdown of caspase-10 or caspase-8 in a human cell line resulted in the reduction of inflammatory cytokine production. Cells derived from caspase-8-deficient mice also showed reduced expression of inflammatory cytokines as well as NF-B activation. Furthermore, the Fas-associated death domain protein interacted with these two caspases and IFN- promoter stimulator 1. These results indicate that caspase-8 and caspase-10 are essential components that mediate NF-B-dependent inflammatory responses in antiviral signaling.

	Introduction

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Host defense against viral infection depends on the detection of viral components by host pattern recognition receptors and the subsequent production of type I IFN (IFN- and IFN-) (1). Transcription of IFN- is tightly regulated by cooperative activation of transcription factors such as NF-B, activating transcription factor-2/c-Jun, IFN regulatory factor (IRF)² 3, and IRF7 (1). Whereas NF-B and activating transcription factor-2/c-Jun are activated by numerous stimuli and regulate the expressions of genes required for inflammation, IRF3 and IRF7 mainly regulate type I IFN expression. NF-B is sequestered in cytoplasm by interacting with IBs. Virus infection triggers IB kinase -mediated phosphorylation and the subsequent degradation of IBs, allowing NF-B to translocate into the nuclei (2). IRF3 and IRF7 also reside in the cytoplasm in resting cells. Upon viral infection, these IRFs are phosphorylated by TANK-binding kinase 1 and IB kinase i and translocated into the nucleus to regulate gene expression (3, 4, 5).

TLR3, TLR7, and TLR9 recognize viral nucleic acids such as dsRNA, ssRNA, and DNA, respectively (6, 7). However, dsRNA is also recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene (Mda) 5 (8, 9, 10, 11). These helicases contain two caspase recruitment domains (CARDs) that mediate the activation of NF-B, IRF3, and IRF7. It has been suggested that the CARD-containing IFN- promoter stimulator (IPS) 1 (also known as MAVS, VISA, or Cardif) serves as an adapter for these helicases (12, 13, 14, 15). Fas-associated death domain (FADD) and receptor-interacting protein (RIP) 1, which interact with TNFR family members (16), have been shown to be involved in antiviral responses (17). IPS-1 also interacts with FADD and RIP1 (12); however, downstream events of IPS-1 and the roles of FADD and RIP1 in antiviral signaling remain unclear.

In the present study we demonstrate that caspase-8 and caspase-10, initiator caspases interacting with FADD, are involved in RIG-I- and Mda5-mediated signaling.

	Materials and Methods

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Cell culture and reagents

Fadd^+/+, Fadd^–/–, caspase-8^+/+, and caspase-8^–/– mouse embryonic fibroblasts (MEFs), which are in mixed genetic background of 129/C57BL6, were prepared as described previously (17, 18, 19). For poly(I:C) stimulation, HEK293 cells or MEFs were transfected with 3.0 µg/ml poly(I:C) (Amersham Biosciences) using Lipofectamine 2000 (Invitrogen Life Technologies) or FuGENE6 (Roche), respectively. Recombinant TNF- and IL-1 were purchased from R&D Systems. Anti-p65 Ab was purchased from Santa Cruz Biotechnology.

Yeast two-hybrid screening

Yeast two-hybrid screening was performed as described previously (20). Full length human FADD was cloned in frame into GAL4 DNA-binding domain of pGBKT7 to use as bait.

Plasmids

Full-length human caspase-10a, caspase-10c that encodes death effector domain (DED), caspase-8b, caspase-8b DED (aa 1–179), FADD, and RIP1 were amplified by PCR from a human spleen cDNA library and cloned into pFLAG-CMV (Sigma-Aldrich). Mutant caspase-10 (D219A) and caspase-8 (D210A/D216A) were generated by using a QuikChange XL site-directed mutagenesis kit (Stratagene). Expression constructs of RIG-I C, Mda5, the TIR domain-containing adaptor inducing IFN- (TRIF), IPS-1, TNFR-associated factor (TRAF) 6, MyD88, IRF7 238–408, and the IFN- promoter-reporter construct were described previously (12, 20). The endothelial cell leukocyte adhesion molecule (ELAM) 1 promoter-driven NF-B luciferase reporter plasmid was provided by Dr. D. T. Golenbock (University of Massachusetts Medical School, Worcester, MA).

Transfection, immunoprecipitation, immunoblot, and reporter analyses

Transfection, immunoprecipitation, immunoblot, extraction of nuclear protein and reporter assays were performed as described previously (12, 20).

RNA interference

The following dsRNA duplexes composed of 21-nt sense and antisense oligonucleotides were synthesized by Dharmacon Research: caspase-10 sense, 5'-CAUUGGUAUUCCAGUUCAGdTdT-3'; caspase-10 antisense, 5'-CUGAACUGGAAUACCAAUGdTdT-3'; caspase-8 sense, 5'-AAGCAAGAACCCAUCAAGGdTdT-3'; caspase-8 antisense, 5'-CCUUGAUGGGUUCUUGCUUdTdT-3'. Transfection of small interfering RNA (siRNA) into HEK293 cells was performed as described previously (12). Knockdown was verified by RT-PCR with following primers; caspase-10, 5'-ATGAAATCTCAAGGTCAA-3' and 5'-CTATAATGAAAGTGCATC-3'; caspase-8, 5'-ATGGACTTCAGCAGAAAT-3' and 5'-TCAATCAGAAGGGAAGAC-3'.

RT-PCR

Total RNA was isolated with TRIzol reagent (Invitrogen Life Technologies) and reverse transcribed with SuperScript III reverse transcriptase (Invitrogen Life Technologies). PCR was subsequently performed with gene-specific primers. Primer sequences are available upon request.

	Results and Discussion

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FADD is involved in IFN- and NF-B activation induced by dsRNA stimulation

Using FADD-deficient MEFs, we examined gene induction after transfection with poly(I:C), a synthetic dsRNA that is used to mimic viral infection. Wild-type MEFs induced Ifnb, Tnfa, and Il-6 in response to poly(I:C), whereas the induction was severely impaired in FADD-deficient MEFs as examined by RT-PCR analyses (Fig. 1A). The induction of Il-6 in response to IL-1 was similar between wild-type and FADD-deficient cells, showing the specificity (Fig. 1A). Because TLR3 is not involved in cytoplasmic poly(I:C) recognition, this response is most likely to be mediated by the RIG-I/Mda5-mediated pathway (5). We next investigated whether or not FADD is involved in the IPS-1-mediated pathway. Although activation of the IFN- promoter by IPS-1 overexpression was reduced in FADD-deficient MEFs, promoter activation by IRF7 238–408 (constitutive active form) (20) was relatively normal (Fig. 1B). Furthermore, activation of the NF-B-responsive ELAM1 promoter by IPS-1 overexpression was also reduced in the absence of FADD, whereas ELAM1 promoter activation by TRAF6 overexpression was normal (Fig. 1C). These results showed that FADD is involved in IPS-1-mediated activation of IFN- promoter and NF-B.

View larger version (38K): [in this window] [in a new window]   FIGURE 1. FADD is required for antiviral responses. A, Wild-type (WT) or FADD-deficient (Fadd–/–) MEFs were stimulated with 3.0 µg/ml poly(I:C) (pIC) or 10 ng/ml IL-1 for the indicated periods. Cells were analyzed by RT-PCR for expression of Ifnb, Tnfa, Il-6, or Actb. B and C, Wild-type (WT) or FADD-deficient (KO, knockout) MEFs were transiently cotransfected with 500 ng of IPS-1 or IRF7 238–408 expression plasmid along with IFN promoter plasmid (B) or 500 ng of IPS-1 or TRAF6 along with ELAM1 promoter plasmid (C), followed by measurement of the luciferase activity. The data are representative of three independent experiments. CNTL, control.

We next performed yeast two-hybrid screening using full-length human FADD as bait. We isolated two genes encoding caspase-10 and one encoding RIP1 (data not shown). Human caspase-10 shows strong homology to human caspase-8 and functions as an initiator caspase in death receptor-mediated signaling (21, 22, 23), allowing us to investigate the role of caspase-10 and caspase-8 in antiviral signaling.

When HEK293 cells transfected with FLAG-caspase-8 were stimulated with poly(I:C), a processed 41-kDa band was observed with anti-FLAG Ab (Fig. 2A). A similar band was also found in TNF--stimulated cells (Fig. 2A). Caspase-10 was also processed into a 43-kDa protein by poly(I:C) stimulation (Fig. 2A).

View larger version (38K): [in this window] [in a new window]   FIGURE 2. Processing of caspase-8 (Casp8) and caspase-10 (Casp10) by poly(I:C) stimulation. A. HEK293 cells were transiently transfected with 2.0 µg of FLAG-caspase-8 (upper panel, lanes 2–5) or FLAG-caspase-10 (lower panel, lanes 2–4). After 24 h, cells were unstimulated (unstim) or stimulated with poly(I:C) (pIC) or TNF- (20 ng/ml). Cell lysates were immunoprecipitated with anti-FLAG followed by blotting with anti-FLAG mAb. B, HEK293 cells were transiently transfected with caspase-10 full-length (FL) or DED (left panel, counting from the left: lanes 2 and 5, 5 ng; lanes 3 and 6, 10 ng; lanes 4 and 7, 50 ng; lane 1 is control) or with caspase-8 full-length (FL) or DED (right panel, counting from the left: lanes 2 and 5, 1 ng; lanes 3 and 6, 5 ng; lanes 4 and 7, 50 ng; lane 1 is control) along with an ELAM1 promoter. The luciferase activity was measured 36 h after transfection. The data are representative of three independent experiments. C, HEK293 cells were transiently transfected with control (CNTL), caspase-10 full-length (FL), caspase-10 DED, caspase-8 full-length (FL), caspase-8 DED, or IPS-1 expression plasmid. Total RNA was prepared 24 h after transfection and analyzed for expressions of Tnfa, Il-8, Ifnb, or Gapdh by RT-PCR. D and E, HEK293 cells were transiently transfected with (E, counting from the left: lanes 1, 4, and 7) increasing amounts of expression plasmid encoding FADD (D, left panel) or RIP1 (D, right panel) (D, counting from the left: lanes 2, 1 ng; lanes 3, 10 ng; lanes 4, 50 ng; lanes 1 are control (CNTL)) along with ELAM1 promoter (D) or 10 ng of FADD, 10 of ng RIP1, or 300 ng of TRAF6 in combination with control plasmid or increasing amounts of caspase-10 D219A (E, left panel) or caspase-8 D210A/D216A (E, right panel) (E, counting from the left: lanes 2, 5, and 8, 1 ng; lanes 3, 6, and 9, 10 ng; lanes 1 are control) along with ELAM1 promoter (E). Thirty-six hours after transfection the luciferase activity of cell lysates was measured. The data are representative of three independent experiments.

Overexpression of FADD and RIP1 also activated the ELAM1 promoter (Fig. 2D). We generated mutants of caspase-10 and caspase-8 that had amino acid substitutions between the prodomain and protease domain (D219A in caspase-10 and D210A/D216A in caspase-8). These mutants can no longer be cleaved to release DEDs. Overexpression of these mutants clearly inhibited the ELAM1 promoter activation induced by FADD and RIP1 but had no effect on TRAF6-mediated ELAM-1 promoter activation (Fig. 2E), strongly suggesting that the processing of these caspases is required for activation of downstream signaling.

Caspase-10 and caspase-8 are required for dsRNA-induced NF-B activation

We prepared double-stranded 21-mer RNAs targeting human caspase-10 and caspase-8 mRNAs that reduced endogenous expression of caspase-10 and caspase-8 in HEK293 cells (Fig. 3A). In caspase-10 knocked-down cells, expression of Tnfa and Il-6 after poly(I:C) stimulation was reduced (Fig. 3B). In contrast, induction of Ifnb and Cxcl10, which encodes IFN--inducible protein 10, was relatively normal (Fig. 3B). Similar results were observed in caspase-8 knocked-down cells (Fig. 3B). Overexpression of RIG-I C, which is a constitutively active form (8), or of Mda5 resulted in induction of Tnfa and Il-6, and induction of these genes was reduced in caspase-10- and caspase-8 knocked-down cells (Fig. 3C). Activation of the ELAM1 promoter by IPS-1 overexpression was also reduced in caspase-10- and caspase-8 knocked-down cells (Fig. 3D). In contrast, these siRNAs had no effect on activation of ELAM1 promoter induced by TRIF (Fig. 3D). IPS-1-induced IFN- prompter activation was not influenced by treatment with caspase-10 and caspase-8 siRNA (data not shown).

View larger version (53K): [in this window] [in a new window]   FIGURE 3. The physiological functions of caspase-10 (Casp10) and caspase-8 (Casp8) in dsRNA-mediated antiviral responses. A, HEK293 cells treated with siRNA targeting caspase-10 and caspase-8 were analyzed by RT-PCR for expression of Casp10, Casp8 or Gapdh. B, HEK293 cells treated with the indicated siRNA were stimulated with poly(I:C) for 3 h followed by analyzed expression of Tnfa, Il-6, Ifnb, Cxcl10, or Gapdh by RT-PCR. CNTL, control. C, HEK293 cells treated with the indicated siRNA were transiently transfected with 600 ng of RIG-I C or Mda5. Twenty-four hours after transfection, total RNA was prepared and analyzed for expression of Tnfa, Il6, or Gapdh by RT-PCR. CNTL, control. D, HEK293 cells treated with the indicated siRNA were transiently cotransfected with 800 ng of IPS-1 (left panel) or TRIF (right panel) along with the ELAM1 promoter plasmid. Thirty-six hours after transfection the luciferase activity of cell lysates was measured. The data are representative of three independent experiments. CNTL, control.

Whereas human cells express caspase-8 and caspase-10, murine cells do not express caspase-10 (23); therefore, we used cells derived from caspase-8-deficient mice to examine antiviral responses. Although activation of IFN- promoter by poly(I:C) stimulation was severely impaired in FADD-deficient cells, the activation was relatively normal in caspase-8-deficient cells (Fig. 4A). Consistently, Ifnb mRNA induction after poly(I:C) stimulation was not impaired in caspase-8-deficient cells (Fig. 4B). However, the induction of Tnfa and Il-6 was severely impaired after 2 h of poly(I:C) stimulation and reduced after 6 h of stimulation in caspase-8-deficient cells (Fig. 4B). Il-6 induction after IL-1 stimulation was not impaired in caspase-8-deficient cells (Fig. 4B). Furthermore, nuclear translocation of p65, a component of NF-B, was reduced in caspase-8-deficient cells (Fig. 4C). Activation of the ELAM1 promoter by IPS-1 was also reduced in caspase-8-deficient cells, whereas activation was normal when MyD88 was overexpressed (Fig. 4D). In contrast, IFN- promoter activation by IPS-1 was normal in caspase-8-deficient cells (Fig. 4E). These results suggest that caspase-8 is specifically involved in IPS-1-mediated NF-B activation.

View larger version (38K): [in this window] [in a new window]   FIGURE 4. Impaired inflammatory responses by dsRNA stimulation in caspase-8-deficient cells. A, MEFs derived from wild type (WT), FADD-deficient (Fadd–/–) or caspase-8-deficient (Casp8–/–) mice were transiently transfected with the IFN- promoter plasmid. After 24 h, cells were left unstimulated or stimulated with poly(I:C). The luciferase activity of cell lysates was measured 24 h after treatment. The data are representative of three independent experiments. B, Wild-type (WT) or caspase-8-deficient (Casp8–/–) MEFs stimulated with poly(I:C) (pIC) or IL-1 for indicated periods were analyzed by RT-PCR for expression of Ifnb, Tnfa, Il-6, or Actb. C, Wild-type (WT) or caspase-8-deficient (Casp8–/–) MEFs were left unstimulated (0 h) or stimulated with poly(I:C) (pIC) for 2 or 6 h. Nuclear proteins were prepared and analyzed by immunoblot (IB) with anti-p65. D and E, WT or caspase-8-deficient (KO, knockout) MEFs were cotransfected with 500 ng of IPS-1 or MyD88 along with ELAM1 promoter plasmid (D) or 500 ng of IPS-1 along with IFN- promoter plasmid (E), followed by measurement of the luciferase activity. The data are representative of three independent experiments. CNTL, control.

Our recent study on IPS-1 demonstrated that FADD is involved in NF-B activation downstream of IPS-1, because FADD overexpression induced NF-B activation but not IRF3 activation, and FADD DED blocked IPS-1-mediated NF-B activation (12). However, activation of IFN- and NF-B promoters in response to dsRNA was significantly reduced in FADD-deficient cells. These results suggest that FADD is required for both NF-B and IRF3 activation in murine fibroblast cells. Although structure-based analyses on the interactions among IPS-1, FADD, and caspase-8/10 is still required, this study showed that caspase-8 and caspase-10 are involved in RIG-I/Mda5-dependent antiviral immune responses, particularly inflammatory responses.

	Acknowledgments

 
We thank G. Barber for providing Fadd^–/– MEFs. We also thank K. J. Ishii, Y. Torii, and C. Coban for useful discussions, A. Miyabe and A. Shibano for technical assistance, and M. Hashimoto for secretarial assistance.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp

² Abbreviations used in this paper: IRF, IFN regulatory factor; DED, death effector domain; ELAM, endothelial cell leukocyte adhesion molecule; FADD, Fas-associated death domain; IPS, IFN- promoter stimulator; Mda, melanoma differentiation-associated gene; MEF, mouse embryonic fibroblast; RIG-I, retinoic acid-inducible gene I; RIP, receptor-interacting protein; siRNA, small interfering RNA; TRAF, TNFR-associated factor; TRIF, TIR domain-containing adaptor inducing IFN-.

Received for publication December 23, 2005. Accepted for publication February 10, 2006.

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Top Abstract Introduction Materials and Methods Results and Discussion Disclosures References

 

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