IL-7 regulation of cytotoxic lymphocytes: Pore-forming protein gene expression, interferon-γ production, and cytotoxicity of human peripheral blood lymphocyte subsets

Smyth, Mark J.; Norihisa, Y; Gerard, Jeffrey R.; Young, Howard A.; Ortaldo, John R.

doi:10.1016/0008-8749(91)90163-6

Cited by 52 publications

(30 citation statements)

References 36 publications

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“…IL-8 is a member of the CXC chemokine family that plays an important role in autoimmune, inflammatory, and infectious diseases (22)(23)(24). Because of its potent proinflammatory properties, IL-8 is tightly regulated, and its expression is low or undetectable in normal tissues.…”

Section: Discussionmentioning

confidence: 99%

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Binsky

Haran

Starlets

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

154

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Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-B activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8-dependent survival pathway.apoptosis ͉ invariant chain B cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of CD5 ϩ B lymphocytes in peripheral blood, lymphoid organs, and bone marrow (1). The hallmark of the disease is decreased apoptosis, resulting in accumulation of these malignant cells. Previous studies have shown that chronic lymphocytic leukemia (CLL) lymphocytes express relatively large amounts of mRNA for CD74, which is the cell-surface form of invariant chain (Ii), as compared with normal B cells (2, 3). CD74 is a nonpolymorphic type II integral membrane protein, which was originally thought to function mainly as an MHC class II chaperone (4). However, CD74 recently was found to play an additional role as an accessory-signaling molecule. In macrophages, CD74 demonstrates high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74; this complex is required for MIF-mediated MAPK activation and cell proliferation (5). Moreover, the bacterium Helicobacter pylori was shown to bind to CD74 on gastric epithelial cells and to stimulate IL-8 production (6).In a previous study, we showed that CD74 is involved directly in shaping the B cell repertoire (7, 8) by a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105 (9). NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which translocates to the cell nucleus (10). This signal is terminated by degradation of the active CD74-ICD fragment (11,12). Moreover, we demonstrated recently that CD74 stimulation with an agonistic CD74 antibody leads to NF-B activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of members of the Bcl-2 protein family. Thus, these findings indicate that surface CD74 functions as a survival receptor (13).In the present study, we sought to determine whether CD74 functions as a survival receptor in B-CLL cells. Our results show that MIF-induced CD74 activation initiates a signaling cascade that results in secr...

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Section: Discussionmentioning

confidence: 99%

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Binsky

Haran

Starlets

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

154

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“…IL-7 was originally identified as a stromally derived growth factor for B cells (27), and subsequently has been shown to have several different roles. These include lymphopoiesis (28), survival (14,29), quiescence (30,31), enhancing the cytolytic function of mature T cells (32), and cell cycling both in RTEs (6, 12) and mature T cells following suboptimal stimulation with anti-CD3 Abs in vitro (33,34). In initial experiments, we confirmed that proliferation of RTEs in response to IL-7 is dose dependent (data not shown), in which a single dose can induce long-term survival of RTEs (data not shown).…”

Section: Discussionmentioning

confidence: 99%

IL-7-Regulated Homeostatic Maintenance of Recent Thymic Emigrants in Association with Caspase-Mediated Cell Proliferation and Apoptotic Cell Death

O’Neill

Hassan

Reen

2003

The Journal of Immunology

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Homeostasis of T cells is essential to the maintenance of the T cell pool and TCR diversity. In this study, mechanisms involved in the regulation of cytokine-mediated expansion of naive T cells in the absence of Ag, in particular the role of caspase activation and susceptibility to apoptosis of recent thymic emigrants (RTEs), were examined. Low level caspase-8 and caspase-3 activation was detected in proliferating IL-7-treated cells in the absence of cell death during the first days of culture. Caspase inhibitors suppressed IL-7-induced expansion of RTEs. Low level expression of CD95 and blocking Ab experiments indicated that this early caspase activation was CD95 independent. However, CD95 levels subsequently became dramatically up-regulated on proliferating naive T cells, and these cells became susceptible to CD95 ligation, resulting in high level caspase activation and apoptotic cell death. These results show a dual role for caspases in proliferation and in CD95-induced cell death during Ag-independent expansion of RTEs. This method of cell death in IL-7-expanded RTEs is a previously unrecognized mechanism for the homeostatic control of expanded T cells.

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“…IL-8, originally identified as a chemotactic factor for leukocytes, belongs to CXC chemotactic cytokine family, and has been demonstrated to play important roles in pathogenesis of autoimmune and inflammatory diseases (Smyth et al, 1991;Koch et al, 1992;Mukaida et al, 1998). Its expression is therefore tightly controlled in cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells

et al. 2004

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IL-7 regulation of cytotoxic lymphocytes: Pore-forming protein gene expression, interferon-γ production, and cytotoxicity of human peripheral blood lymphocyte subsets

Cited by 52 publications

References 36 publications

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

IL-7-Regulated Homeostatic Maintenance of Recent Thymic Emigrants in Association with Caspase-Mediated Cell Proliferation and Apoptotic Cell Death

Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells

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