Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia

Abstract

Abstract. Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and the development of myeloid cells and their precursors in the blood and bone marrow. Interleukin 35 (IL-35), a novel inhibitory cytokine secreted by regulatory T (Treg) cells is a novel potential target used for the therapeutic manipulation of Treg activity in order to treat cancer and autoimmune diseases. To investigate the role and imbalance of Treg-related cytokines in the pathogenesis of AML, we measured the plasma concentration of three Treg-associated cytokines [IL-35, IL-10 and transforming growth factor-β (TGF-β)] and evaluated their clinical relevance. The concentration of IL-35, IL-10 and TGF-β in plasma specimens from 55 patients with AML [27 newly diagnosed (ND) patients and 28 in complete remission (CR)] and 24 controls was analyzed using the enzyme-linked immunosorbent assay method. Significantly higher levels of plasma IL-35 and IL-10 were observed in AML ND patients compared with healthy controls or AML CR patients. IL-10 concentrations were positively correlated with TGF-β, whereas no correlations were found between the other cytokines. IL-10 levels were positively correlated with white blood cell (WBC) and neutrophil (NEU) count but there were no correlations between IL-35 and TGF-β with WBC and NEU count. In conclusion, we demonstrated for the first time that AML ND patients have increased plasma concentrations of IL-35, suggesting that this cytokine is involved in the pathophysiological process of the disease, and that further research is required to address this issue. IntroductionAcute myeloid leukemia (AML) is a life-threatening hematopoietic stem cell neoplasm characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation, frequently resulting in fatal infection, bleeding or organ infiltration, with or without leukocytosis (1-3). The etiology of AML is heterogeneous and complex, but it is widely accepted that both environmental and genetic factors play significant roles in the development of the disease. Immune system disorders have increased our understanding of leukemogenesis (4). However, little is known about the pathogenic events leading to the initiation and progression of this disease. Previously, elevated levels of regulatory T (Treg) cells in a variety of hematological malignancies including AML have been reported (5-8). Patients with a lower Treg cell frequency at diagnosis have a better response to induction chemotherapy and a favorable prognosis (6,8).Treg + Treg cells, which are present in the normal immune system, engage in the maintenance of natural self-tolerance and also the control of immune responses to foreign antigens (9).IL-35, a member of the IL-12 family, is a recently identified heterodimeric cytokine consisting of Epstein-Barr virusinduced gene protein 3 (EBI3) and the p35 subunit of . In contrast to all other known IL-12 family members, which are not expressed by T cells, IL-35...

IL-35 expression in peripheral blood CD4+ T cells from chronic hepatitis B virus-infected patients directly correlates with virus load

“…to the severity of the disease [28][29][30]. These findings indicate that inflammatory mediators can induce IL-35 expression in human tissues and indeed this was confirmed by a separate study in which anti-CD3/CD28 were used to stimulate human T regs, and high amounts of soluble IL-35 were induced [31].…”

Baicalin from the extract of Scutellaria baicalensis affects the innate immunity and apoptosis in leukocytes of children with acute lymphocytic leukemia

“…Also, an increased level of IL-10 in serum after treatment with baicalin was noticed in an animal model of heatstroke [39]. Significantly higher levels of plasma IL-10 were observed in AML patients compared with healthy controls or AML patients in complete remission [40]. Similarly, a higher level of IL-10 was determined in cell culture supernatants from B-ALL and T-ALL patients in comparison to those in the controls [41].…”

Islet antigen-pulsed dendritic cells expressing ectopic IL-35Ig protect nonobese diabetic mice from autoimmune diabetes

“…More recently, other IL-35-producing cells have been identified, such as tumor antigen (Ag)-specific CD8 + CTLA-4 + Treg cells [16] and B cells after acquiring suppressive function upon stimulation via TLR4 and CD40 [17]. In addition, several studies have demonstrated IL-35 being expressed in different tumors [15,18,19], whereby it promotes angiogenesis and neoplastic growth by suppressing anti-tumor immunity [20]. Nevertheless, exogenous administration of rIL-35, or its ectopic expression (i.e., in cells normally nonexpressing the cytokine), was found to be protective in pathological conditions such as overwhelming inflammation combined with uncontrolled autoimmune responses, namely CIA [12], experimental autoimmune encephalomyelitis (EAE) [21], autoimmune diabetes [22], inflammatory bowel disease [15,23], atherosclerosis [24] and allergic airway inflammation [25].…”