TY - JOUR
T1 - The drug monosodium luminol (GVT) preserves crypt-villus epithelial organization and allows survival of intestinal T cells in mice infected with the ts1 retrovirus
AU - Scofield, Virginia L.
AU - Yan, Mingshan
AU - Kuang, Xianghong
AU - Kim, Soo Jin
AU - Wong, Paul K.Y.
N1 - Funding Information:
We thank Shawna Johnson and Rebecca Deen for assistance in preparing the manuscripts, Kent Claypool for providing invaluable help with flow cytometry analysis, and Nancy Otto and Jimi Lynn Brandon of the Science Park Histology Core for preparing excellent frozen sections and for advising us regarding immunohistochemical analysis. This work was supported by NIH grants NS43984 and MH71583 (P.K.Y.), by a Career Re-entry supplement to MH71583 for V.L.S., and by NIH grant MH077470 (V.L.S.). Other support was provided by NIEHS Center Grant ES07784 and Core Grant CA16672, both to the M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX, by the Dr. Christian Abee of the Michale E. Keeling Center for Comparative Medicine and Research, The University of Texas M.D. Anderson Cancer Center, Bastrop, TX, and by the Longevity Foundation of Austin.
PY - 2009/2/21
Y1 - 2009/2/21
N2 - Of the cytopathic retroviruses that affect mammals, including HIV-1, many selectively infect CD4+ T cells and cause immunosuppressive syndromes. These diseases destroy both the thymus and the small and large intestines, after infecting and killing T-lineage cells in both tissues. A mutant of the murine leukemia retrovirus MoMuLV-TB, called ts1, causes this syndrome in susceptible strains of mice. In FVB/N strain mice that are infected at birth, thymic atrophy, CD4+ T cell loss, intestinal collapse, body wasting, and death occur by ∼30-40 days postinfection (dpi). Apoptosis of ts1-infected T-lineage cells, in the thymus, peripheral lymphoid system and intestines is caused by accumulation of the ts1 mutant viral envelope preprotein gPr80env, which is inefficiently cleaved into the mature viral proteins gp70 and PrP15E. We show here that ts1 infection in the small intestine is followed by loss of intestinal epithelial cell (IEC) thyroid-stimulating hormone (TSH) and cell cycling gradients (along the crypt-villus axes), accumulation of gPr80env in intestinal cells, apoptosis of developing T cells in the lamina propria (LP), and intestinal collapse by ∼30 dpi. In infected mice treated with the antioxidant drug monosodium luminol (GVT®), however, normal intestinal epithelial cell gradients are still in place at 30 dpi, and IECs covering both the crypts and villi contain large amounts of the antioxidant transcription factor Nrf2. In addition, no apoptotic cells are present, and accumulated gpr80env is absent from the tissue at this time. We conclude that GVT treatment can make ts1 a noncytopathic virus for intestinal lymphoid cells, as it does for thymocytes [25]. As in the thymus, GVT may protect the intestine by reducing oxidant stress in infected intestinal T cells, perhaps by prevention of gPr80env accumulation via Nrf2 upregulation in the IECs. These results identify GVT as a potential therapy for intestinal diseases or inflammatory conditions, including HIV-AIDS, in which oxidative stress is a triggering or exacerbating factor.
AB - Of the cytopathic retroviruses that affect mammals, including HIV-1, many selectively infect CD4+ T cells and cause immunosuppressive syndromes. These diseases destroy both the thymus and the small and large intestines, after infecting and killing T-lineage cells in both tissues. A mutant of the murine leukemia retrovirus MoMuLV-TB, called ts1, causes this syndrome in susceptible strains of mice. In FVB/N strain mice that are infected at birth, thymic atrophy, CD4+ T cell loss, intestinal collapse, body wasting, and death occur by ∼30-40 days postinfection (dpi). Apoptosis of ts1-infected T-lineage cells, in the thymus, peripheral lymphoid system and intestines is caused by accumulation of the ts1 mutant viral envelope preprotein gPr80env, which is inefficiently cleaved into the mature viral proteins gp70 and PrP15E. We show here that ts1 infection in the small intestine is followed by loss of intestinal epithelial cell (IEC) thyroid-stimulating hormone (TSH) and cell cycling gradients (along the crypt-villus axes), accumulation of gPr80env in intestinal cells, apoptosis of developing T cells in the lamina propria (LP), and intestinal collapse by ∼30 dpi. In infected mice treated with the antioxidant drug monosodium luminol (GVT®), however, normal intestinal epithelial cell gradients are still in place at 30 dpi, and IECs covering both the crypts and villi contain large amounts of the antioxidant transcription factor Nrf2. In addition, no apoptotic cells are present, and accumulated gpr80env is absent from the tissue at this time. We conclude that GVT treatment can make ts1 a noncytopathic virus for intestinal lymphoid cells, as it does for thymocytes [25]. As in the thymus, GVT may protect the intestine by reducing oxidant stress in infected intestinal T cells, perhaps by prevention of gPr80env accumulation via Nrf2 upregulation in the IECs. These results identify GVT as a potential therapy for intestinal diseases or inflammatory conditions, including HIV-AIDS, in which oxidative stress is a triggering or exacerbating factor.
KW - GVT
KW - Intestine
KW - Oxidative stress
KW - Retrovirus
UR - http://www.scopus.com/inward/record.url?scp=61849111203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61849111203&partnerID=8YFLogxK
U2 - 10.1016/j.imlet.2008.12.012
DO - 10.1016/j.imlet.2008.12.012
M3 - Article
C2 - 19186189
AN - SCOPUS:61849111203
VL - 122
SP - 150
EP - 158
JO - Immunology Letters
JF - Immunology Letters
SN - 0165-2478
IS - 2
ER -