Interleukin-11 induces Th2 polarization of human CD4+ T cells

Abstract

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 ''...

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

“…Murine L cells stably transfected with the human CD40L (CD154) cDNA 49,50 were cultured in RPMI 1640 (Cambrex Bio Science, Verviers, Belgium) supplemented with penicillin/streptomycin, L-glutamine, and 10% heat-inactivated FCS (Cambrex Bio Science). Isolated CLL B cells were cocultured with CD40L-transfected cells in 24-well plates for 72 hours.…”

“…39 PBMCs were isolated by density gradient centrifugation (Ficoll; Biochrom, Berlin, Germany) and subjected to a preliminary phenotypic characterization. When residual non-B cells exceeded 10%, B cells were enriched by negative selection with antibody-coated magnetic beads (CD2-beads; Dynal, Oslo, Norway) to obtain a more than 95% pure CD19 ϩ /CD5 ϩ B-cell population.Murine L cells stably transfected with the human CD40L (CD154) cDNA 49,50 were cultured in RPMI 1640 (Cambrex Bio Science, Verviers, Belgium) supplemented with penicillin/streptomycin, L-glutamine, and 10% heat-inactivated FCS (Cambrex Bio Science). Isolated CLL B cells were cocultured with CD40L-transfected cells in 24-well plates for 72 hours.…”

IL-11 Induces Th17 Cell Responses in Patients with Early Relapsing-Remitting Multiple Sclerosis

“…Similar to IL-6, IL-11 induces STAT3 phosphorylation in several noninflammatory cell subsets (26)(27)(28)(29) and induces autoreactive Ab production by B cells (30). Several studies have reported on the IL-11 anti-inflammatory effects, including the inhibition of NF-kBmediated cytokine secretion in macrophages (31,32) and monocytes (22), and the induction of apoptosis in myeloid dendritic cells (23,33). However, in the recent literature, IL-11 has been strongly implicated as a proinflammatory cytokine because of its induction by oxidative stress (34), its production by synoviocytes in rheumatoid arthritis (35), and by eosinophils in atopic dermatitis (36).…”

“…Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 is a pleiotropic cytokine (21)(22)(23) and a member of the IL-6 family, with which it shares a gp130 signaling pathway (24). IL-11 competes with IL-6 for binding to the same gp130 epitopes and induces the same early response genes (25).…”

Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437–460

“…Such modulation was potentially promoted by the simultaneous decrease in levels of TNF␣ and IL-7, both key antagonists of Treg cell-induced immunoregulation (46). Down-regulation of CD40, IL-10, and IL-11 (47) may further suggest that Th2-associated responses were modulated by treatment. An effect of Hsp60 on B cells through innate signaling pathways has been reported (48) and may also contribute to the modulation of autoimmune diseases with a confirmed or potential B cell aspect.…”