Ikuko Haruta

The A-domain is a approximately 200-amino acid peptide present within structurally diverse proadhesive proteins including seven integrins. A recombinant form of the A-domain of beta 2 integrins CR3 and LFA-1 has been recently shown to bind divalent cations and to contain binding sites for protein ligands that play essential roles in leukocyte trafficking to inflammatory sites, phagocytosis and target cell killing. In this report we demonstrate that the neutrophil adhesion inhibitor, NIF produced by the hookworm Ancyclostoma caninium is a selective CD11b A-domain binding protein. NIF bound directly, specifically and with high affinity (Kd of approximately 1 nM) to recombinant CD11b A-domain (r11bA). The binding reaction was characterized by rapid association and very slow dissociation, and was blocked by an anti-r11bA monoclonal antibody. No binding was observed to rCD11aA. The NIF-r11bA interaction required divalent cations, and was absent when the mutant r11bA D140GS/AGA (that lacks divalent cation binding capacity) was used. The NIF binding site in r11bA was mapped to four short peptides, one of which being an iC3b binding site. The interaction of NIF with CR3 in intact cells followed similar binding kinetics to those with r11bA, and occurred with similar affinity in resting and activated human neutrophils, suggesting that the NIF epitope is activation independent. Binding of NIF to CR3 blocked its ability to bind to its ligands iC3b, fibrinogen, and CD54, and inhibited the ability of human neutrophils to ingest serum opsonized particles. NIF thus represents the first example of a disintegrin that targets the integrin A-domain, and is likely to be used by the hookworm to evade the host's inflammatory response. The unique structure of NIF, which lacks a disintegrin motif, emphasizes basic structural differences in antagonists targeting A+ and A- integrins, that should be valuable in drug design efforts aimed at generating novel therapeutics. Identification of the region in NIF mediating A-domain binding should also be useful in this regard, and may, as in the case of disintegrins, unravel a new structural motif with cellular counterparts mediating important physiologic functions.

We present a patient with massive tarry stool, diagnosed as duodenal varices bleeding. Endoscopic ligation (EL) therapy was carried out for the varices, but because the possibility of re-bleeding remained, we treated the varices with balloon-occluded retrograde transvenous obliteration (BRTO), and duodenal varices were successfully decompressed without any complications. BRTO might be a novel therapeutic approach for ectopic varices, including duodenal varices.

Propionic acidemia (PA) is an inborn error of metabolism caused by the genetic deficiency of propionyl-CoA carboxylase (PCC). By disrupting the alpha-subunit gene of PCC, we created a mouse model of PA (PCCA(-/-)), which died in 24-36 h after birth due to accelerated ketoacidosis. A postnatal, liver-specific PCC expression via a transgene in a far lower level than that in wild-type liver, allowed PCCA(-/-) mice to survive the newborn and early infant periods, preventing a lethal fit of ketoacidosis (SAP(+)PCCA(-/-) mice). Interestingly, SAP(+)PCCA(-/-) mice, in which the transgene expression increased after the late infant period, continued to grow normally while mice harboring a persistent low level of PCC died in the late infant period due to severe ketoacidosis, clearly suggesting the requirement of increased PCC supplementation in proportion to the animal growth. Based on these results, we propose a two-step strategy to achieve an efficient PA prevention in human patients: a partial PCC supplementation in the liver during the newborn and early infant periods, followed by a larger amount of supplementation in the late infant period.

A hallmark of many inflammatory diseases is the destruction of tissue cells by infiltrating hematopoietic cells including lymphocytes, neutrophils, and macrophages. The regulation of apoptosis of both target tissue cells and the infiltrating cells is one of the key events that defines the initiation and the progression of inflammation. However, the precise picture of the apoptosis regulation of the cells at the inflammatory sites is still unclear. We recently isolated a novel apoptosis inhibitory factor, termed AIM, which is secreted exclusively by tissue macrophages. In this report, we present unique characteristics of AIM associated with liver inflammation (hepatitis), identified by introducing an experimental hepatitis in both AIM-transgenic mice, which overexpress AIM in the body, and normal mice. First, endogenous AIM expression in macrophages is rapidly increased in response to inflammatory stimuli. Second, AIM appears to inhibit the death of macrophages in the inflammatory regions, judging by the remarkably increased number of macrophages observed in the liver from transgenic mice. In addition, we show that AIM also enhances the phagocytosis by macrophages, which emphasizes the multifunctional character of AIM. All these findings strongly provoke an idea that AIM may play an important role in hepatitis pathogenesis in a sequential manner; first AIM expression is up-regulated by inflammatory stimuli, and then in an autocrine fashion, AIM supports the survival of infiltrating macrophages as well as enhances phagocytosis by macrophages, which may result in an efficient clearance of dead cells and infectious or toxic reagents. A hallmark of many inflammatory diseases is the destruction of tissue cells by infiltrating hematopoietic cells including lymphocytes, neutrophils, and macrophages. The regulation of apoptosis of both target tissue cells and the infiltrating cells is one of the key events that defines the initiation and the progression of inflammation. However, the precise picture of the apoptosis regulation of the cells at the inflammatory sites is still unclear. We recently isolated a novel apoptosis inhibitory factor, termed AIM, which is secreted exclusively by tissue macrophages. In this report, we present unique characteristics of AIM associated with liver inflammation (hepatitis), identified by introducing an experimental hepatitis in both AIM-transgenic mice, which overexpress AIM in the body, and normal mice. First, endogenous AIM expression in macrophages is rapidly increased in response to inflammatory stimuli. Second, AIM appears to inhibit the death of macrophages in the inflammatory regions, judging by the remarkably increased number of macrophages observed in the liver from transgenic mice. In addition, we show that AIM also enhances the phagocytosis by macrophages, which emphasizes the multifunctional character of AIM. All these findings strongly provoke an idea that AIM may play an important role in hepatitis pathogenesis in a sequential manner; first AIM expression is up-regulated by inflammatory stimuli, and then in an autocrine fashion, AIM supports the survival of infiltrating macrophages as well as enhances phagocytosis by macrophages, which may result in an efficient clearance of dead cells and infectious or toxic reagents. lipopolysaccharide recombinant AIM Apoptosis is a form of cell death that is achieved by programmed signal cascades triggered by differential stimuli depending on the variety of physiological situations (1Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar, 2Pombo C.M. Bonventre J.V. Avruch J. Woodgett J.R. Kyriakis J.M. Force T. J. Biol. Chem. 1994; 269: 26546-26551Abstract Full Text PDF PubMed Google Scholar, 3Westwick J.K. Bielawska A.E. Dbaibo G. Hannun Y.A. Brenner D.A. J. Biol. Chem. 1995; 270: 22689-22692Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 4Verheij M. Bose R. Lin X.H. Yao B. Jarvis W.D. Grant S. Birrer M.J. Szabo E. Zon L.I. Kyriakis J.M. Haimovitz-Friedman A. Fuks Z. Kolesnick R.N. Nature. 1996; 380: 75-79Crossref PubMed Scopus (1710) Google Scholar). Accumulating evidence has revealed that apoptosis plays a key role in the pathology of inflammation (5Steller H. Science. 1995; 267: 1445-1449Crossref PubMed Scopus (2422) Google Scholar, 6Jacobson M.D. Weil M. Raff M.C. Cell. 1997; 88: 347-354Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 7Raff M.C. Nature. 1992; 356: 397-400Crossref PubMed Scopus (2488) Google Scholar, 8Vaux D.L. Haecker G. Strasser A. Cell. 1994; 76: 777-779Abstract Full Text PDF PubMed Scopus (688) Google Scholar, 9Thompson C.B. Science. 1995; 267: 1456-1462Crossref PubMed Scopus (6173) Google Scholar, 10Cory S. Annu. Rev. Immunol. 1995; 13: 513-543Crossref PubMed Scopus (398) Google Scholar, 11Yang E. Korsmeyer S.J. Blood. 1996; 88: 386-401Crossref PubMed Google Scholar, 12Strasser A. Huang D.C. Vaux D.L. Biochim. Biophys. Acta. 1997; 1333: 151-178PubMed Google Scholar, 13Chao D.T. Korsmeyer S.J. Annu. Rev. Immunol. 1998; 16: 395-419Crossref PubMed Scopus (1499) Google Scholar). The present consensus is emerging that both positive (inducing) and negative (inhibiting) regulation of apoptosis of tissue cells influence the initiation and the progression of tissue damage (14Reed J. Curr. Opin. Oncol. 1995; 7: 541-546Crossref PubMed Scopus (486) Google Scholar, 15Rothstein T.L. Curr. Opin. Immunol. 1996; 8: 362-371Crossref PubMed Scopus (35) Google Scholar, 16Nishina H. Fischer K.D. Radvanyi L. Shahinian A. Hakem R. Rubie E.A. Bernstein A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; 385: 350-353Crossref PubMed Scopus (308) Google Scholar, 17Irmler M. Thome M. Hahne M. Schneider P. Hofmann K. Steiner V. Bodmer J.L. Schroter M. Burns K. Mattmann C. Rimoldi D. French L.E. Tschopp J. Nature. 1997; 388: 190-195Crossref PubMed Scopus (2211) Google Scholar). It has been indicated that apoptosis at the inflammatory sites seems to be induced by: 1) inflammatory cytokines produced by the infiltrating hematopoietic cells as well as the tissue epithelium cells (18Benoist C. Mathis D. Cell. 1997; 89: 1-3Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 19Andre I. Gonzalez A. Wang B. Katz J. Benoist C. Mathis D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2260-2263Crossref PubMed Scopus (280) Google Scholar, 20Wang B. Gonzalez A. Benoist C. Mathis D. Eur. J. Immunol. 1996; 26: 1762-1769Crossref PubMed Scopus (199) Google Scholar) and 2) interaction of CD95 (also called Fas) on the tissue cells and CD95 ligand (CD95L) predominantly expressed on infiltrating T-lymphocytes (21Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar, 22Liu W. Tan D. Zhang Z. Fan X. Ouyang K. Chung-Hua Kan Tsang Ping Tsa Chih. 2000; 8: 269-271Google Scholar, 23Hahn C.S. Cho Y.G. Kang B.S. Lester I.M. Hahn Y.S. Virology. 2000; 276: 127-137Crossref PubMed Scopus (115) Google Scholar, 24Taya N. Torimoto Y. Shindo M. Hirai K. Hasebe C. Kohgo Y. Br. J. Haematol. 2000; 10: 89-97Crossref Scopus (51) Google Scholar, 25Crispe I.N. Dao T Klugewitz K. Mehal W.Z. Metz D.P. Immunol. Rev. 2000; 174: 47-62Crossref PubMed Scopus (275) Google Scholar, 26Ogawa S. Sakaguchi K. Takaki A. Shiraga K. Sawayama T. Mouri H. Miyashita M. Koide N. Tsuji T. J. Gastroenterol. Hepatol. 2000; 15: 69-7513Crossref PubMed Scopus (26) Google Scholar, 27Ji W. Wang H. Feng C. Chung-Hua Kan Tsang Ping Tsa Chih. 1999; 7: 77-79Google Scholar). In particular, the prevention of endotoxin-induced hepatitis by the defect of CD95/CD95L ligation strongly implies that CD95-mediated apoptosis of hepatocytes is the initial event in the process of hepatitis (21Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar). In addition to apoptosis of tissue cells, apoptosis regulation of infiltrating cells also seems to influence the progression of inflammation. This indication was recently drawn by the observation of non-obese diabetic mice, a mouse model of human autoimmune diabetes (type I diabetes), under CD95-deficient conditions, which were free from destruction of insulin-producing pancreatic β cells by the infiltrating T-lymphocytes. In these mice, a defect of CD95 appeared to decrease apoptotic death of T-lymphocytes infiltrating into the pancreatic Langerhans islets, resulting in the prevention of tissue damage (28Kim Y.H. Kim S. Kim K.A. Yagita H Kayagaki N. Kim K.W. Lee M.S. Eur. J. Immunol. 1999; 29: 455-465Crossref PubMed Scopus (93) Google Scholar, 29Kim S. Kim K.A. Hwang D.Y. Lee T.H. Kayagaki N. Yagita H. Lee M.S. J. Immunol. 2000; 15: 2931-2936Crossref Scopus (85) Google Scholar). Thus, the regulation of both target tissue cells and infiltrating cells influence the progression of inflammatory diseases.However, we are essentially ignorant of the negative (inhibitory) regulation of apoptosis at the inflammatory sites, although apoptosis must be regulated both positively and negatively, and the balance of these two regulations may critically influence the inflammation progression. This is mainly because the extracellular ligands produced at the inflammatory sites that mediate inhibitory signals for apoptosis have not been well defined so far despite the recent identification of many intracellular apoptosis inhibitory elements (14Reed J. Curr. Opin. Oncol. 1995; 7: 541-546Crossref PubMed Scopus (486) Google Scholar, 15Rothstein T.L. Curr. Opin. Immunol. 1996; 8: 362-371Crossref PubMed Scopus (35) Google Scholar, 16Nishina H. Fischer K.D. Radvanyi L. Shahinian A. Hakem R. Rubie E.A. Bernstein A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; 385: 350-353Crossref PubMed Scopus (308) Google Scholar, 17Irmler M. Thome M. Hahne M. Schneider P. Hofmann K. Steiner V. Bodmer J.L. Schroter M. Burns K. Mattmann C. Rimoldi D. French L.E. Tschopp J. Nature. 1997; 388: 190-195Crossref PubMed Scopus (2211) Google Scholar).We recently isolated a novel murine apoptosis inhibitory factor, termed AIM, which is exclusively secreted by tissue macrophages including Kupffer cells in the liver (30Miyazaki T. Hirokami Y. Matsuhashi N. Takatsuka H. Naito M. J. Exp. Med. 1999; 189: 413-422Crossref PubMed Scopus (141) Google Scholar, 31Yusa S. Ohnishi S. Onodera T. Miyazaki T. Eur. J. Immunol. 1999; 29: 1086-1093Crossref PubMed Google Scholar). AIM inhibits apoptosis triggered by multiple stimuli including irradiation, glucocorticoid, and CD95-cross-linking (30Miyazaki T. Hirokami Y. Matsuhashi N. Takatsuka H. Naito M. J. Exp. Med. 1999; 189: 413-422Crossref PubMed Scopus (141) Google Scholar). At the inflammatory sites of most tissues, the macrophage is one of the cell types that is observed from the very early stage of inflammation (32Papaccio G. De Luca B. Pisanti F.A. J. Cell. Biochem. 1998; 71: 479-490Crossref PubMed Scopus (11) Google Scholar, 33Yoon J.W. Jun H.S. Arch. Pharmacol. Res. 1999; 22: 437-447Crossref PubMed Scopus (28) Google Scholar, 34Jun H.S. Santamaria P. Lim H.W. Zhang M.L. Yoon J.W. Diabetes. 1999; 48: 34-42Crossref PubMed Scopus (78) Google Scholar, 35Rosmalen J.G. Martin T. Dobbs C. Voerman J.S. Drexhage H.A. Haskins K. Leenen P.J. Lab. Invest. 2000; 80: 23-30Crossref PubMed Scopus (49) Google Scholar, 36Jun H.S. Yoon C.S. Zbytnuik L. van Rooijen N. Yoon J.W. J. Exp. Med. 1999; 189: 347-358Crossref PubMed Scopus (226) Google Scholar). Hence it is possible that AIM might play a role in the negative regulation of apoptosis of cells at the inflammatory sites.In this report, we applied a mouse hepatitis model to address potential involvement of AIM in the progression of inflammation in vivo. In addition, we present a new AIM function associated with inflammation, enhancement of the phagocytic function of macrophages, and discuss the multifunctional character of AIM. Apoptosis is a form of cell death that is achieved by programmed signal cascades triggered by differential stimuli depending on the variety of physiological situations (1Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar, 2Pombo C.M. Bonventre J.V. Avruch J. Woodgett J.R. Kyriakis J.M. Force T. J. Biol. Chem. 1994; 269: 26546-26551Abstract Full Text PDF PubMed Google Scholar, 3Westwick J.K. Bielawska A.E. Dbaibo G. Hannun Y.A. Brenner D.A. J. Biol. Chem. 1995; 270: 22689-22692Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 4Verheij M. Bose R. Lin X.H. Yao B. Jarvis W.D. Grant S. Birrer M.J. Szabo E. Zon L.I. Kyriakis J.M. Haimovitz-Friedman A. Fuks Z. Kolesnick R.N. Nature. 1996; 380: 75-79Crossref PubMed Scopus (1710) Google Scholar). Accumulating evidence has revealed that apoptosis plays a key role in the pathology of inflammation (5Steller H. Science. 1995; 267: 1445-1449Crossref PubMed Scopus (2422) Google Scholar, 6Jacobson M.D. Weil M. Raff M.C. Cell. 1997; 88: 347-354Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 7Raff M.C. Nature. 1992; 356: 397-400Crossref PubMed Scopus (2488) Google Scholar, 8Vaux D.L. Haecker G. Strasser A. Cell. 1994; 76: 777-779Abstract Full Text PDF PubMed Scopus (688) Google Scholar, 9Thompson C.B. Science. 1995; 267: 1456-1462Crossref PubMed Scopus (6173) Google Scholar, 10Cory S. Annu. Rev. Immunol. 1995; 13: 513-543Crossref PubMed Scopus (398) Google Scholar, 11Yang E. Korsmeyer S.J. Blood. 1996; 88: 386-401Crossref PubMed Google Scholar, 12Strasser A. Huang D.C. Vaux D.L. Biochim. Biophys. Acta. 1997; 1333: 151-178PubMed Google Scholar, 13Chao D.T. Korsmeyer S.J. Annu. Rev. Immunol. 1998; 16: 395-419Crossref PubMed Scopus (1499) Google Scholar). The present consensus is emerging that both positive (inducing) and negative (inhibiting) regulation of apoptosis of tissue cells influence the initiation and the progression of tissue damage (14Reed J. Curr. Opin. Oncol. 1995; 7: 541-546Crossref PubMed Scopus (486) Google Scholar, 15Rothstein T.L. Curr. Opin. Immunol. 1996; 8: 362-371Crossref PubMed Scopus (35) Google Scholar, 16Nishina H. Fischer K.D. Radvanyi L. Shahinian A. Hakem R. Rubie E.A. Bernstein A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; 385: 350-353Crossref PubMed Scopus (308) Google Scholar, 17Irmler M. Thome M. Hahne M. Schneider P. Hofmann K. Steiner V. Bodmer J.L. Schroter M. Burns K. Mattmann C. Rimoldi D. French L.E. Tschopp J. Nature. 1997; 388: 190-195Crossref PubMed Scopus (2211) Google Scholar). It has been indicated that apoptosis at the inflammatory sites seems to be induced by: 1) inflammatory cytokines produced by the infiltrating hematopoietic cells as well as the tissue epithelium cells (18Benoist C. Mathis D. Cell. 1997; 89: 1-3Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 19Andre I. Gonzalez A. Wang B. Katz J. Benoist C. Mathis D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2260-2263Crossref PubMed Scopus (280) Google Scholar, 20Wang B. Gonzalez A. Benoist C. Mathis D. Eur. J. Immunol. 1996; 26: 1762-1769Crossref PubMed Scopus (199) Google Scholar) and 2) interaction of CD95 (also called Fas) on the tissue cells and CD95 ligand (CD95L) predominantly expressed on infiltrating T-lymphocytes (21Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar, 22Liu W. Tan D. Zhang Z. Fan X. Ouyang K. Chung-Hua Kan Tsang Ping Tsa Chih. 2000; 8: 269-271Google Scholar, 23Hahn C.S. Cho Y.G. Kang B.S. Lester I.M. Hahn Y.S. Virology. 2000; 276: 127-137Crossref PubMed Scopus (115) Google Scholar, 24Taya N. Torimoto Y. Shindo M. Hirai K. Hasebe C. Kohgo Y. Br. J. Haematol. 2000; 10: 89-97Crossref Scopus (51) Google Scholar, 25Crispe I.N. Dao T Klugewitz K. Mehal W.Z. Metz D.P. Immunol. Rev. 2000; 174: 47-62Crossref PubMed Scopus (275) Google Scholar, 26Ogawa S. Sakaguchi K. Takaki A. Shiraga K. Sawayama T. Mouri H. Miyashita M. Koide N. Tsuji T. J. Gastroenterol. Hepatol. 2000; 15: 69-7513Crossref PubMed Scopus (26) Google Scholar, 27Ji W. Wang H. Feng C. Chung-Hua Kan Tsang Ping Tsa Chih. 1999; 7: 77-79Google Scholar). In particular, the prevention of endotoxin-induced hepatitis by the defect of CD95/CD95L ligation strongly implies that CD95-mediated apoptosis of hepatocytes is the initial event in the process of hepatitis (21Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar). In addition to apoptosis of tissue cells, apoptosis regulation of infiltrating cells also seems to influence the progression of inflammation. This indication was recently drawn by the observation of non-obese diabetic mice, a mouse model of human autoimmune diabetes (type I diabetes), under CD95-deficient conditions, which were free from destruction of insulin-producing pancreatic β cells by the infiltrating T-lymphocytes. In these mice, a defect of CD95 appeared to decrease apoptotic death of T-lymphocytes infiltrating into the pancreatic Langerhans islets, resulting in the prevention of tissue damage (28Kim Y.H. Kim S. Kim K.A. Yagita H Kayagaki N. Kim K.W. Lee M.S. Eur. J. Immunol. 1999; 29: 455-465Crossref PubMed Scopus (93) Google Scholar, 29Kim S. Kim K.A. Hwang D.Y. Lee T.H. Kayagaki N. Yagita H. Lee M.S. J. Immunol. 2000; 15: 2931-2936Crossref Scopus (85) Google Scholar). Thus, the regulation of both target tissue cells and infiltrating cells influence the progression of inflammatory diseases. However, we are essentially ignorant of the negative (inhibitory) regulation of apoptosis at the inflammatory sites, although apoptosis must be regulated both positively and negatively, and the balance of these two regulations may critically influence the inflammation progression. This is mainly because the extracellular ligands produced at the inflammatory sites that mediate inhibitory signals for apoptosis have not been well defined so far despite the recent identification of many intracellular apoptosis inhibitory elements (14Reed J. Curr. Opin. Oncol. 1995; 7: 541-546Crossref PubMed Scopus (486) Google Scholar, 15Rothstein T.L. Curr. Opin. Immunol. 1996; 8: 362-371Crossref PubMed Scopus (35) Google Scholar, 16Nishina H. Fischer K.D. Radvanyi L. Shahinian A. Hakem R. Rubie E.A. Bernstein A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; 385: 350-353Crossref PubMed Scopus (308) Google Scholar, 17Irmler M. Thome M. Hahne M. Schneider P. Hofmann K. Steiner V. Bodmer J.L. Schroter M. Burns K. Mattmann C. Rimoldi D. French L.E. Tschopp J. Nature. 1997; 388: 190-195Crossref PubMed Scopus (2211) Google Scholar). We recently isolated a novel murine apoptosis inhibitory factor, termed AIM, which is exclusively secreted by tissue macrophages including Kupffer cells in the liver (30Miyazaki T. Hirokami Y. Matsuhashi N. Takatsuka H. Naito M. J. Exp. Med. 1999; 189: 413-422Crossref PubMed Scopus (141) Google Scholar, 31Yusa S. Ohnishi S. Onodera T. Miyazaki T. Eur. J. Immunol. 1999; 29: 1086-1093Crossref PubMed Google Scholar). AIM inhibits apoptosis triggered by multiple stimuli including irradiation, glucocorticoid, and CD95-cross-linking (30Miyazaki T. Hirokami Y. Matsuhashi N. Takatsuka H. Naito M. J. Exp. Med. 1999; 189: 413-422Crossref PubMed Scopus (141) Google Scholar). At the inflammatory sites of most tissues, the macrophage is one of the cell types that is observed from the very early stage of inflammation (32Papaccio G. De Luca B. Pisanti F.A. J. Cell. Biochem. 1998; 71: 479-490Crossref PubMed Scopus (11) Google Scholar, 33Yoon J.W. Jun H.S. Arch. Pharmacol. Res. 1999; 22: 437-447Crossref PubMed Scopus (28) Google Scholar, 34Jun H.S. Santamaria P. Lim H.W. Zhang M.L. Yoon J.W. Diabetes. 1999; 48: 34-42Crossref PubMed Scopus (78) Google Scholar, 35Rosmalen J.G. Martin T. Dobbs C. Voerman J.S. Drexhage H.A. Haskins K. Leenen P.J. Lab. Invest. 2000; 80: 23-30Crossref PubMed Scopus (49) Google Scholar, 36Jun H.S. Yoon C.S. Zbytnuik L. van Rooijen N. Yoon J.W. J. Exp. Med. 1999; 189: 347-358Crossref PubMed Scopus (226) Google Scholar). Hence it is possible that AIM might play a role in the negative regulation of apoptosis of cells at the inflammatory sites. In this report, we applied a mouse hepatitis model to address potential involvement of AIM in the progression of inflammation in vivo. In addition, we present a new AIM function associated with inflammation, enhancement of the phagocytic function of macrophages, and discuss the multifunctional character of AIM. We thank Dr. Sumiko Yamakawa and Itoe Okamoto Foundation for financial support, Dr. Shin Ohnishi (Tokyo, Japan) for discussions. The Basel Institute for Immunology was founded and supported by Hoffmann-La Roche Ltd, Basel Switzerland.