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NEWS AND VIEWS The observation that the DC conditioning requires the soluble T cell products IL-4 and IL-10, but does not affect neighboring DCs, is new and intriguing. The authors speculate that a focused cytokine release may occur within the spatial constraints of the ‘immunological synapse’, the defined interface between T cells and DCs required for structured cross-talk. Nevertheless, a recent study shows that previously activated CD4+ T cells, though restricted by major histocompatibility (MHC) class II recognition on DCs, can activate neighboring MHC-II-deficient DCs through engagement of CD40 and secretion of IL-2 (ref. 16). It is therefore possible that the spatial limitations are a function of the precise magnitude of the effector response and quality of the conditioning T cell as well as the pattern of costimulatory molecule expression by DCs14,17. In this respect, Alpan et al. demonstrate, using a
new two-step in vitro culture system, that direct cell-cell contact is required during the conditioning of the DC, in addition to IL-4 and IL-10. In the future, it will be important to determine if CD4+ T cell responses induced by conditioned DCs in vitro can be protective in autoimmune diseases and transplantation. If so, defining the precise DC phenotype at the molecular level in response to different classes of ‘educating’ T cells could serve several purposes: effective in vitro generation and expansion of regulatory T cells for immunotherapy, direct use of conditioned DCs to achieve specific immune modulation of T cell responses in vivo, and identification of pharmacological targets for directed control of DC function. 1. Mestecky, J. & McGhee, J.R. Curr. Top. Microbiol. Immunol. 146, 3–11 (1989). 2. Weiner, H.L. et al. Annu. Rev. Immunol. 12, 809–837 (1994). 3. Mowat, A.M. Nat. Rev. Immunol. 3, 331–341 (2003).
4. Homann, D. et al. Immunity 11, 463–472 (1999). 5. Alpan, O., Bachelder, E., Isil, E., Arnheiter, H. & Matzinger, P. Nat. Immunol. 5, 615–622 (2004). 6. Cobbold, S. & Waldmann, H. Curr. Opin. Immunol. 10, 518–524 (1998). 7. Tian, J. et al. Infectious Th1 and Th2 autoimmunity in diabetes-prone mice. Immunol. Rev. 164, 119–127 (1998). 8. Bennett, S.R., Carbone, F.R., Karamalis, F., Miller, J.F. & Heath, W.R. J. Exp. Med. 186, 65–70 (1997). 9. Mitchison, N.A. & O’Malley, C. Eur. J. Immunol. 17, 1579–1583 (1987). 10. Cassell, D. & Forman, J. Ann. N. Y. Acad. Sci. 532, 51–60 (1988). 11. Bennett, S.R. et al. Nature 393, 478–480 (1998). 12. Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R. & Melief, C.J. Nature 393, 480–483 (1998). 13. Ridge, J.P., Di Rosa, F. & Matzinger, P. Nature 393, 474–478 (1998). 14. Gerloni, M. et al. Proc. Natl. Acad. Sci. USA 97, 13269–13274 (2000). 15. Honey, K., Cobbold, S.P. & Waldmann, H. J. Immunol. 163, 4805–4810 (1999). 16. Behrens, G.M. et al. J. Immunol. 172, 5420–5426 (2004). 17. King, C. et al. Nat. Med. 7, 206–214 (2001).
Cheating death in the liver M Eugenia Guicciardi & Gregory J Gores The FDA-approved drug suramin is best known for combating trypanosome infection. Now it takes on the liver, where it prevents apoptosis and fends off damage in mouse models of hepatitis (pages 602–609). Liver health depends on the efficient removal of unwanted cells, such as aged or virusinfected cells, mainly through apoptosis. In a physiologic setting, new cells generated by mitosis replace those that are eliminated, ensuring organ homeostasis. An alteration in this balance between cell death and proliferation can cause liver diseases such as cancer or hepatitis, depending on whether the balance is tilted toward proliferation or apoptosis. Excessive apoptosis after acute injury results in destruction of extensive areas of liver tissue1, whereas persistent, moderately high apoptosis leads to fibrosis and perhaps cirrhosis2. Given the poor prognosis and high mortality rates associated with most liver diseases, a therapy to reduce apoptosis in this organ has important clinical applications. In this issue, Eichhorst et al.3 suggest that suramin, a drug approved by the US Food and Drug Administration for the treatment of the parasitic infection trypanosomiasis, is effec-
M Eugenia Guicciardi & Gregory J Gores are in the Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. e-mail:
[email protected]
tive in reducing death receptor–mediated apoptosis in vitro in selected cell lines and in vivo in a mouse model of acute hepatitis. Apoptosis can be triggered by activation of two molecular pathways: an intrinsic, mitochondrialy mediated cascade and an extrinsic process mediated by death receptors at the cell surface. In the liver, the second pathway seems to be the most common. Death receptors are cytokine receptors with structural similarities to tumor necrosis factor receptor-1 (TNF-R1). The most widely expressed members of the family are Fas (also called CD95 or APO-1), TNF-R1, and TNF-related apoptosis-inducing ligand receptor-1 and -2 (TRAIL-R1, or DR4, and TRAIL-R2, or DR5). When engaged by their natural ligands, these receptors trigger intracellular cascades that activate death-inducing proteolytic enzymes, especially caspases. The molecular pathways activated by death receptors have been extensively studied. Signaling by Fas, probably the best characterized so far, is initiated by receptor oligomerization induced by the engagement of Fas ligand (Fig. 1). The receptor aggregate facilitates recruitment of the adaptor Fas-associated protein with death domain (FADD), which, in turn, associates with the proforms
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of initiator caspase-8 and caspase-10. This association promotes self-processing and activation of the initiator caspases and their dissociation from the protein complex. The receptor caspase-activating complex is often referred to as the death-inducing signaling complex (DISC). When generated in large amounts by the DISC, the mobile, active initiatior caspases directly activate downstream caspases and cause cell death; this is termed type I signaling. When the initiator caspase-8 and -10 are generated in smaller amounts by the DISC, signaling through a mitochondrial amplification loop is required for cytotoxicity; this is termed type II signaling. Hepatocytes undergo Fas-mediated apoptosis through type II signaling cascades4. Several studies in humans and animals have shown that hepatocyte apoptosis in acute and chronic liver diseases is generally mediated by death receptors, in particular Fas5. Evolutionary pressures may have conspired to render the hepatocyte supersensitive to Fas-mediated cytotoxicity so that viruses can be efficiently eradicated by cytotoxic T-lymphocytes. Indeed, hepatocytes are quite sensitive to Fas killing by cytotoxic T lymphocytes, but are uniquely resistant to granule-mediated killing (involving perforin
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Procaspase-8 and -10 Death receptor pathway
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Figure 1 Fas signaling and progression of liver disease. Engagement of the Fas receptor by its cognate ligand (FasL) triggers recruitment of the adaptor protein FADD and initiator caspase-8 and caspase-10, generating the death-inducing signaling complex (DISC). Initiator caspases are activated at the DISC by self-processing and can cleave and activate downstream caspases (such as caspase-3) either directly or indirectly (through a mitochondrial amplification loop). These downstream caspases degrade cellular substrates. The amount of active caspase-8 generated at the DISC determines whether the cell activates a mitochondrial-independent (type I) or mitochondrial-dependent (type II) pathway of caspase activation and apoptosis. The mitochondrial amplification loop is triggered by caspase-8 cleavage of Bid, which, in turn, prompts release of cytochrome c and Apaf-1 from mitochondria and facilitates caspase-9 activation. Eichhorst et al.3 report that attenuation of Fasmediated apoptosis by the FDA-approved drug suramin may help slow, or even prevent, the progression of liver disease.
and granzyme B)6. Consistent with the sensitivity of the liver to Fas cytotoxicity, in vivo administration of Fas-activating antibodies to mice selectively induces acute liver failure7. Likewise, Fas-mediated apoptosis has been associated with liver fibrosis in more chronic models8. The latter observation suggests that inhibiting death receptor–mediated apoptosis could prevent the progression of chronic liver injury (such as the development of liver cirrhosis and portal hypertension) (Fig. 1). Blocking Fas signaling with small interfering RNA (siRNA) targeting the genes encoding either Fas itself or caspase-8 reduces hepatitis in acute models of liver
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injury and the progression of fibrosis in more chronic models9,10. The applicability of such an approach to clinical studies, however, has yet to be established. Eichhorst et al. overcome the problems that accompany new therapeutic strategies by using suramin, a drug already approved for treatment of various diseases. The authors describe for the first time its antiapoptotic effect against death receptor–mediated apoptosis in type II– but not type I–signaling cells. In a series of elegant experiments, the authors demonstrate that the antiapoptotic effect of suramin is due to reduced activa-
tion of initiator caspase-8 and -10 within the DISC. The effect is indirect, as the DISC forms normally but is dysfunctional with regard to full caspase-8 and -10 processing. Suramin should prove a useful tool to further dissect the DISC inhibitory pathway and thereby provide mechanistic and therapeutic information. Most remarkably, the authors also show that suramin is effective in reducing Fas- and TNF-α-mediated apoptotic liver damage in mice, improving liver functions and increasing animal viability. Although the new data are certainly intriguing, a few concerns remain regarding the real therapeutic potential of suramin in the treatment of human liver diseases. Although suramin clearly works in preventing apoptosis when administered at the same time as the apoptotic stimuli, there are data to show that treatment with suramin may be beneficial in reducing ongoing liver damage, the most frequent situation clinicians have to face. Unfortunately, patients and physicians seldom have the opportunity to use preemptive therapies. On the contrary, the known inhibitory effect of suramin on several growth factors might result in impairment of liver cell regeneration after damage, and may actually be detrimental in a disease process also requiring repair and tissue restitution11,12. Moreover, suramin seems to have opposite effects on different tissues, which could represent a problem when systemically administered. However, as its ability to block apoptosis seems to be restricted to type II–signaling cells, its antiapoptotic effect would be limited to epithelial-based organs such as the liver. Knowledge of the structure of this molecule and further work examining how it prevents apoptosis should provide tools for developing liver-targeted antiapoptotic therapies. Such hepatoprotective therapies could be useful in acute liver injury to save lives, and in chronic liver injury to minimize hepatic fibrosis. 1. Schuchmann, M. & Galle, P.R. Eur. J. Gastroenterol. Hepatol. 13, 785–790 (2001). 2. Canbay, A., Friedman, S. & Gores, G.J. Hepatology 39, 273–278 (2004). 3. Eichhorst, S.T. et al. Nat. Med. 10, 602–609 (2004). 4. Scaffidi, C. et al. EMBO J. 17, 1675–1687 (1998). 5. Galle, P.R. & Krammer, P.H. Semin. Liver Dis. 18, 141–151 (1998). 6. Kafrouni, M.I., Brown, G.R. & Thiele, D.L. J. Immunol. 167, 1566–1574 (2001). 7. Ogasawara, J. et al. Nature 364, 806–809 (1993). 8. Canbay, A. et al. Gastroenterology 123, 1323–1330 (2002). 9. Zender, L. et al. Proc. Natl. Acad. Sci. USA 100, 7797–7802 (2003). 10. Song, E. et al. Nat. Med. 9, 347–351 (2003). 11. Eisenberger, M.A. & Reyno, L.M. Cancer Treat. Rev. 20, 259–273 (1994). 12. Michalopoulos, G.K. FASEB J. 4, 176–187 (1990).
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