Fas Ligand-dependent and -independent mechanisms of toxicity induced by T cell lymphomas in lymphoid organs and in the liver.
In the current study, we investigated the effect of growth of FasL(+) tumors in vivo on the functions of peripheral lymphoid organs and the liver. Injection of FasL(+) LSA tumor cells into syngeneic C57BL/6 wild-type mice but not C57BL/6 lpr/lpr (Fas-deficient) mice caused apoptosis in splenocytes. Spleen cells expressing CD3, CD4, CD8, CD19, Mac-3, and CD44 were all susceptible to tumor-induced apoptosis. Also, activated T cells were more sensitive to apoptosis induced by LSA tumor cell lysate when compared to naïve T cells. In contrast, anti-Fas Abs (Jo2) induced apoptosis in only activated but not naïve T cells. When the LSA tumor-bearing mice were injected with a superantigen (SEA), these mice showed a significant decrease in the expansion of SEA-reactive Vbeta3(+) and Vbeta11(+) T cells. When injected into syngeneic mice, the FasL(+) LSA tumor cells caused hepatotoxicity, as indicated by an increase in serum aspartate aminotransferase (AST) levels. Interestingly, Fas-deficient C57BL/6 lpr/lpr mice also showed significant AST levels in the serum following LSA tumor growth. Moreover, hepatocytes isolated from C57BL/6 wild-type and C57BL/6 lpr/lpr mice were equally susceptible to apoptosis induced by LSA tumor cell lysate in vitro. Using cDNA array, LSA tumor cells were found to express several cytokine genes including IL-2, IL-7, IL-11, IL-13, IL-16, lymphotoxin beta, and tumor necrosis factor beta. Together, these data suggested that, in mice bearing FasL(+) LSA tumor, the immunotoxicity is FasL-based, whereas the hepatotoxicity, at least in part, may be FasL-independent.
Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Catherine
C
Lombard
Robert J
RJ
McKallip
Philip B
PB
Hylemon
Prakash S
PS
Nagarkatti
Mitzi
M
Nagarkatti
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001219:Aspartate Aminotransferases / Q000097:blood; D002455:Cell Division; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D022781:Hepatocytes / Q000276:immunology; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000276:immunology* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018089:Superantigens; D001219:Aspartate Aminotransferases