Suppression of Hematopoietic Support Function Is Associated with Overexpression of lnterleukin-4 and Transforming Growth Factor-β1 in LP-BM5 Murine-Leukemia-Virus-lnfected Stromal Cell Lines

Abstract

Murine acquired immunodeficiency syndrome (MAIDS) induced by defective LP-BM5 murine leukemia virus (MuLV) is a disease with many similarities to human AIDS. Our previous studies demonstrated that the depressed hematopoiesis observed in LP-BM5-infected marrow cultures could be attributed to a defective hematopoietic stroma. We report now the generation of permanent stroma cell lines from noninfected and LP-BM5-infected marrow cultures. Retrovirus infection was confirmed by the polymerase chain reaction for detecting viral genome expression of the p12 envelope glycoprotein. The ability of these cell lines to support in vitro hematopoiesis was evaluated. The results demonstrated that when cocultured with normal or infected nonadherent mononuclear cells, noninfected cell lines efficiently supported the production of hematopoietic progenitors, whereas in virus-infected cell lines production of both normal and virus-infected progenitors was suppressed. Expression of cytokine genes in stromal cell lines was also examined. All cell lines expressed equivalent levels of transcripts for interleukin (IL)-1β IL-2, IL-3, IL-6, IL-7, IL-10, interferon, tumor necrosis factor-α and stem cell factor. However, infection was associated with higher expression of IL-4 and transforming growth factor-β1. These findings demonstrate that infected stomal cell lines generate a defective hematopoietic microenvironment to produce altered cytokine expression and faulty hematopoiesis. Further characterization of these defective cell lines should assist elucidation of the mechanism(s) whereby retroviruses alter hematopoiesis ultimately leading to the generation of immunodeficiency.

Increased expression of lymphocyte‐derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation

“…These ®ndings may indicate that either PSC and/or PEC are capable of producing IFN-g mRNA. So far, only few SC-lines, primarily derived from thymus [36] and bone marrow [37], and no EC types have been shown to express IFN-g mRNA. With respect to IFN-g, these ®ndings con®rm results from immunohistological stainings of fetal and normal prostates.…”

Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection

“…Th2 cells, in contrast, secrete IL‐4, IL‐6 and IL‐10, which activate antibody production and suppress Th1 cells. In vivo , activated B cells and macrophages from HIV‐infected patients, produced high levels of IL‐6 and TNF‐α, 42 as do LPS‐stimulated splenocytes and peritoneal macrophages in MuLV retrovirus‐infected mice 43 . When IL‐4‐deficient (IL‐4 gene knockout) mice were infected with LP‐BM5 retrovirus, there was no lethality and development of T‐cell abnormalities was delayed 44 .…”

“…Elevated levels of IL‐6 have also been associated with stimulating HIV replication in macrophages and T cells 45 . IFN‐γ administration significantly retarded murine AIDS by preventing activation of Th2 cytokines 43 . Thus, the reduction of Th2 cytokines by hormone supplementation could be a potential treatment for AIDS 27 .…”

Predominant Regeneration of B-Cell Lineage, Instead of Myeloid Lineage, of the Bone Marrow after 1 Gy Whole-Body Irradiation in Mice: Role of Differential Cytokine Expression between B-Cell Stimulation by IL10, Flt3 Ligand and IL7 and Myeloid Suppression by GM-CSF and SCF

“…In irradiated non-SCI mice, expression of the positive regulators of B lymphopoiesis, namely, IL10, Flt3 ligand and IL7 (11,22,23) produced by stromal cells, is generally up-regulated. The IL10 gene expression level in particular increased markedly by 48.2-fold over the pretreatment level 9 days after irradiation ( Fig.…”