The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cellto-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and plateletderived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.
IntroductionInterleukin (IL)-11 is a multifunctional cytokine that was originally isolated from the primate stromal cell line, PU-34, and later from the human MRC 5 cell line. Biologic characterization has shown diverse effects on a variety of hematopoietic and nonhematopoietic cell types (reviewed in reference 1). Due to its ability to stimulate megakaryopoiesis and thrombopoiesis, IL-11 has been approved in the United States for the treatment of chemotherapy-induced thrombocytopenia. In addition to stimulating hematopoietic progenitor cells, 2 IL-11 exerts a strong anti-inflammatory activity in vitro and in vivo. By inhibiting nuclear translocation of nuclear factor-kB (NF-kB), 3 IL-11 reduces production by macrophages of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), IL-1, Therapeutic applications of this effect in multiple animal models of inflammatory disorders have reduced signs of disease. 4,5,[7][8][9] In a well-characterized murine model of graftversus-host disease (GVHD) directed at major histocompatibility complex (MHC) and minor antigens, IL-11 strongly inhibited GVHD and enhanced recipient survival. 10 These effects were due to protection of the small bowel from irradiation and GVHD toxicity, suppression of TNF-␣, and polarization of donor T cells to a Th2 response with decreased interferon-␥ (IFN-␥) and augmented IL-4 production. 10 Interestingly, a significant reduction of CD4-dependent GVHD was not associated with impairment of the cytolytic function and graft-versusleukemia (GVL) effect of CD8 ϩ T cells. 11 Thus, a short course of IL-11 treatment before allogeneic stem cell transplantation has been proposed to help separate the GVL effect from GVHD. 11 Recently, IL-11 therapy has been administered to patients with psoriasis in a phase I clinical dose-escalation trial. 12 The treatment led to down-regulation of type I cytokines in psoriatic lesions and reduction of keratinocyte proliferation and cutaneous inflammation.Taken together, these studies have revealed that IL-11 exerts a series of important immunomodulatory effects that can be applied in various therapeutic contexts. However, the issue as to whether T-cell polarization is solely due to IL-11-mediated suppression of IL-12 or whether IL-11 has additional direct effects on CD4 ϩ CD45RA ϩ naive T cells has yet to be addressed. The most potent antigen-presenting cells (APCs) involved in the stimulation of naive CD4 ϩ cells are dendritic cells (DCs), which induce type I responses by their ability to produce IL-12 on maturation. 13 In this study, we investigated the immunomodulatory effects of IL-11 on monocytes, human monocyte-derived DCs (Mo-DCs), and T cells. Our results demonstrate that IL-11 regulates immune responses by at least 2 potent mechanisms of action: it inhibits IL-12 production by monocytes and exerts a direct effect on CD4 ϩ Th cell polarization. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''...
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