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14 recordsLinked to original sources
PubMed1992

Interleukin (IL1 to IL7) gene expression in fetal liver and bone marrow stromal clones: cytokine-mediated positive and negative regulation.

Mouse bone marrow and fetal liver stromal clones have been analyzed for their cytokine mRNA expression. The reverse transcriptase polymerase chain reaction (RT-PCR) has allowed us to detect interleukin (IL) mRNA levels, even if synthesized at levels not detectable by Northern blot analysis. We found that stromal cells possess the potential to constitutively express a much larger number of interleukins than previously described. The three stromal clones analyzed here expressed mRNA for IL3 and IL2, in addition to mRNA for IL1, IL4, IL6, and IL7. None of the stromal clones synthesized IL5 mRNA. Cytokine mRNA synthesis by stromal cells was found to be subjected to negative and positive regulation by interleukins. IL2, IL3, IL6, and IL7 gene expression was much more sensitive to cytokine regulation than that of IL1 and IL4.

Animals↗
PubMed1989

Interleukin 7 (murine pre-B cell growth factor/lymphopoietin 1) stimulates thymocyte growth: regulation by transforming growth factor beta.

The effects of interleukin 7 (IL7) previously known as murine pre-B cell growth factor/lymphopoietin 1 on the growth of murine thymocytes was investigated. In the presence of a suboptimal dose of phytohemagglutinin, IL7 induced a dose-dependent increase in thymocyte proliferation which was comparable to that induced by IL1. Additionally IL7 was shown to synergize with a suboptimal dose of IL1 to enhance thymocyte proliferation. Thymocyte proliferation induced by IL7, like that induced by IL1, was inhibited when either recombinant transforming growth factor (TGF) beta 1 or beta 2 were added at the initiation of culture. Interestingly, IL7-driven thymocyte proliferation was considerably less susceptible to inhibition by TGF-beta 1 or TGF-beta 2 than that induced by IL1. Taken together these results suggest IL7 may activate distinct populations of thymocytes and/or act through a pathway distinct from that utilized by IL1.

Animals↗
PubMed1991

Human interleukin 7 is a B cell growth factor for activated B cells.

We investigated the capacity of human interleukin (IL)7 to induce proliferation of B cells. Purified tonsillar B cells were cultured in the presence of IL7 with Staphylococcus aureus Cowan I (SAC) or anti-mu beads as co-mitogens. IL7 supported a dose-dependent proliferation of anti-mu-activated B cells but did not significantly support proliferation of SAC-activated B cells. When B cells were separated on Percoll gradient into small (60%-80%) and large (50%-60%) B cells and then cultured with anti-mu beads, IL7 acted on both cell populations equally well. IL7 and BCGF (low molecular weight) were synergistic in their proliferative action on anti-mu-activated B cells in a 5-day culture. On the other hand, synergistic effect of IL7 on activated B cells was not evident in the presence of any other factor recombinant [(r)IL1 beta, rIL2, rIL3, rIL4, rIL5, rIL6, recombinant tumor necrosis factor-alpha, recombinant lymphotoxin, recombinant granulocyte-monocyte colony-stimulating factor and recombinant interferon-gamma] we tested. IL7 did not induce IgG secretion by activated B cells.

Antibodies, Anti-Idiotypic↗
PubMed1992

Interleukin-7 is a growth factor for Sézary lymphoma cells.

Sézary syndrome is a cutaneous T cell lymphoma characterized by infiltration of the skin by CD4+ cells. These cells generally respond poorly to mitogens and T cell activators. We have studied the action of IL1 to IL4, IL6, and IL7 on the proliferation of Sézary cells from 12 patients. With the exception of IL2 and IL7, the cytokines studied had no proliferative effect on these cells. Whereas IL2 had only a low proliferative capacity (two- to threefold increase) on peripheral blood mononuclear cells, recombinant IL7 constantly induced a very significant (3-40-fold increase) proliferative response, and was used successfully to generate cell lines in three out of eight cases. Growth of Sézary cell lines was shown to be strictly dependent on IL7, and after 2-5 wk of culture presented a switch to a homogeneous phenotype CD3+4+8-7- (except for one line that remained CD7+), with a typical morphology of Sézary cells. Their tumoral origin was demonstrated by the expression of the same T cell receptor-beta gene rearrangement as the patients' T cells. Importantly, cultured normal epidermal keratinocyte supernatants could support the growth of our Sézary lines. Furthermore, the proliferative activity contained in these supernatants was completely blocked by a monoclonal anti-IL7 antibody. These results suggest that IL7 may, therefore, represent an important cytokine in the physiopathology of cutaneous T cell lymphoma.

Adult↗
PubMed1991

In vivo evaluation of the effects of interleukins 2, 4 and 7 on enhancing the immunotherapeutic efficacy of anti-tumor cytotoxic T lymphocytes.

The draining lymph nodes of mice injected with viable syngeneic tumor cells contain lymphoid cells capable of generating anti-tumor cytotoxic T lymphocytes (CTL) during a 4-day in vitro culture period and intravenous infusion of relatively low numbers of these CTL can effectively eliminate a challenge of fibrosarcoma cells at distal skin sites that would otherwise result in the death of the host. Using this model system the effects of addition of interleukin (IL) 2, IL4 or IL7 to the culture medium on the therapeutic efficacy of the anti-tumor CTL generated was investigated. In this regard, IL7 was found to be the most potent of the cytokines tested. Addition of IL7 either alone, or in combination with low doses of IL2, resulted in the generation of CTL with significantly (6-8-fold) enhanced therapeutic efficacy in vivo. Anti-tumor effector cells generated in the presence of IL7 were also found to be at least 4-fold more effective at eliminating established tumors than CTL generated in medium alone. Of the other cytokines tested, addition of IL2 resulted in elevated CTL activity in vitro, but only a modest (approximately 2-3-fold) enhancement of the therapeutic efficacy in vivo. Addition of IL4, either alone or in combination with IL2, also resulted in the generation of effector cells with enhanced tumoricidal activity in vitro and yet the therapeutic efficacy of these cells was decreased compared to that of CTL generated in medium alone. These observations indicate that (a) inclusion of IL7 in the medium in which tumor-reactive T cells are cultured can markedly enhance the immunotherapeutic efficacy of the resulting effector cell populations; and (b) in vitro assays of tumoricidal activity cannot be used as a reliable predictor of therapeutic efficacy in vivo.

Animals↗
PubMed1992

Growth and maturation requirements of human B cell precursors.

The present study describes our efforts to induce the proliferation of human B cell precursors (BCP). Committed BCP (CD10+, sIgM-) isolated from fetal bone marrow (18-25 weeks) were induced to proliferate at low levels in the presence of IL7. IL3 potentiated this effect of IL7 on BCP, while IL4 partially inhibited this proliferation. However, neither of these cytokines allowed the emergence of mature B cells. The growth of BCP was strongly potentiated by the presence of an adherent fibroblastic bone marrow stromal layer devoid of cells of hematopoietic origin. Addition of IL7 to such cocultures further increased BCP proliferation. BCP were shown to proliferate as stroma-adherent and non adherent cells. Total cell numbers expanded during 3 weeks, as much as 8 fold in the presence of IL7 when compared with input BCP numbers. Finally, BCP remained sIgM- in stroma dependent cultures, and only a subpopulation of cells became CD20+ in the presence of IL7. Our present study demonstrates the feasibility of human BCP expansion in vitro. However, the signals required for the transition of BCP to mature B cells remain to be determined.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1992

Developmentally regulated cell surface expression and function of c-kit receptor during lymphocyte ontogeny in the embryo and adult mice.

We have used a c-kit-specific monoclonal antibody, immuno-fluorescence staining and flow fluorocytometry or microscopy analysis to assess the cell surface expression of the c-kit receptor on a panel of non-transformed clones representing different stages of T- and B-lymphocyte development, freshly isolated lymphoid cells from thymus, bone marrow and spleen of young adult C57BL/6 mice and cells from yolk sac, thymus and liver of developing C57BL/6 mouse embryos. Pro-T, Pro-B and Pre-B clones derived from thymus or liver of 14-day embryos are c-kit+. Starting at day 8 to 8.5 in yolk sac, day-10 in fetal liver, and day 11 to 12 in fetal thymus, there are many c-kit+ cells. The number of c-kit+ cells in liver and thymus increases up to day 15 and progressively decreases thereafter. Cell sorter purified c-kit+ day 14 fetal liver cells fully reconstitute the T and B cell compartments of immunodeficient Scid mice. Stromal cells or epithelial cells derived from fetal thymus or liver, which can support growth and differentiation of c-kit+ lymphocyte progenitor clones, synthesize mRNA for Steel Factor (SF), the ligand of c-kit. In the adult mouse, however, c-kit expression is restricted to very early stages of T- and B-lymphocyte development (multipotent progenitors, B-cell/myelocytic progenitors, Pro-T and Pro-B lymphocyte progenitors). Most cells at the Pre-T, Pre-B and later stages of development do not bear detectable c-kit. Using Cos-1 cells transfected with mouse SF-cDNA and an antagonistic c-kit receptor-specific antibody, we show that the c-kit/SF system contributes to the survival of lymphocyte progenitors and enhances the proliferative responses of these cells to other growth factors (i.e. IL2, IL3, IL4, IL7). However, the c-kit receptor/SF ligand pair is neither sufficient nor necessary for the differentiation of lymphocyte progenitors into mature T- or B-lymphocytes. Finally, in stromal cell lines from fetal liver and adult bone marrow and thymic epithelial cell lines the level of steady state SF-RNA transcripts is inversely correlated with that of IL-7-mRNA. Moreover, IL7 inhibits the synthesis of SF-mRNA in stromal cells and rIL6 abrogates this inhibitory effect of rIL7. Thus, the expression of SF in stromal cells is subjected to complex regulation by other cytokines produced by the same stromal cells or by neighboring cells in a given microenvironment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗
PubMed1992

The purification of B-cell precursors from mouse fetal liver.

Lymphocyte progenitor cells isolated on sequential days of gestation from mouse fetal liver represent distinct stages in B cell development. We have utilized polymerase chain reaction (PCR)-based assays to detect immunoglobulin (Ig) gene rearrangement and flow cytometry to assay cell surface markers following fractionation based on the differential expression of the B cell-specific phosphatase CD45 (B220). The purification of B220+ cells from day 17 fetal liver resulted in a 10-fold enrichment of cells which had undergone gene rearrangement events. We have also shown that day 13 fetal liver cells activate successive Ig gene rearrangements during short-term culture in the presence of fetal calf serum (FCS), interleukin-3 (IL3), and interleukin-7 (IL7). However, partially purified lymphocyte precursors fail to activate Ig gene rearrangement in culture unless they are cultured in the presence of a stromal cell line.

Animals↗
PubMed2026

Atypical cytokine profiles in people on the autism spectrum: a comprehensive systematic review and meta-analysis including 54 cytokines.

Atypical peripheral blood cytokine concentrations have been shown in autism, but no clear pattern has been observed. This systematic review and meta-analysis summarised current state of findings, expanded the range of cytokines, accounted for study risk of bias, and examined relations between cytokines and autism traits. Literature comparing peripheral blood cytokine in autistic and non-autistic people was systematically searched in Ovid® Embase, MEDLINE and APA PsycINFO, Web of Science™ and Scopus, resulting in 98 studies and 54 cytokines (4236 autistic, 3333 non-autistic controls; age 2 to 65 years) in the meta-analysis. Study risk of bias was assessed using adapted Newcastle-Ottawa Scale. Compared to controls, autistic people had elevated levels of IL1-beta (Hedges' g = 0.620, 95%CI[0.32, 0.92]), IL4 (g = 0.245, 95%CI [0.07, 0.42]), IL6 (g = 0.365, 95%CI [0.011, 0.62]), IL8 (g = 0.384, 95%CI [0.15, 0.62]), IFN-gamma (g = 0.404, 95%CI [0.09, 0.72]), TNF-alpha (g = 0.31, 95%CI [0.11, 0.51]), CXCL1/GRO-α (g = 0.364, 95%CI [0.058, 0.670]) and MIF (g = 0.560, 95%CI [0.14, 0.98]). Over a third of studies were classified as having a high risk of bias; their removal revealed higher IL7 and IL1RA in autism relative to controls. Narrative synthesis produced no strong evidence for an association between cytokine and autism traits among autistic individuals. Altogether, our findings support a predominance of pro-inflammatory cytokines, while also indicating potential modulatory contributions from inhibitory cytokines, which reflect group-level differences between autistic and non-autistic individuals, but not variations of autism traits within the autistic population. However, higher-quality studies with low risk of bias are needed before firm conclusions can be drawn.

Humans↗
PubMed2025

GWAS highlights the neuronal contribution to multiple sclerosis susceptibility.

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the brain and spinal cord. Genetic studies have identified many risk loci, that were thought to primarily impact immune cells and microglia. Here, we performed a multi-ancestry genome-wide association study with 20,831 MS and 729,220 control participants, identifying 236 susceptibility variants outside the Major Histocompatibility Complex, including four novel loci. We derived a polygenic score for MS and, optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 genes affected by MS risk variants. Notably, while T cells showed the strongest enrichment, inhibitory neurons emerged as a key cell type. The expression of IL7 and STAT3 are affected only in inhibitory neurons, highlighting the importance of neuronal and glial dysfunction in MS susceptibility.

Journal Article↗
PubMed1990

Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia.

We investigated the proliferation-inducing effects of human recombinant interleukin-7 (IL-7) on acute lymphoblastic leukemia (ALL) cells. It is shown that IL-7 stimulates DNA synthesis in ALL cells of B-cell precursor (n = 5) as well as immature T-cell origin (n = 2). Cytogenetic analysis of the cells of four patients proliferating in IL7-supplemented cultures established the leukemic descendence of the IL-7-responsive cells. 125I-IL-7 binding experiments with the cells of one patient and with two ALL cell lines showed the presence of two types of IL-7 receptors: one with a high affinity (kd 29 to 51 pmol/L) and one with a low affinity (kd 2.3 to 76 nmol/L) for the ligand. We conclude that IL-7 is one of the cytokines involved in the complex regulation of ALL cell proliferation.

B-Lymphocytes↗