Abstract
IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow.
Highlights
Interleukin 2 (IL-2) is a 15.5 kDa cytokine that is primarily produced by CD4+ T cells following antigen stimulation [1] and to a lesser extent by CD8+ cells [2], NK T cells [3], mast cells [4], monocytes [5], and myeloid dendritic cells [5, 6]
IL-2 increased plasma blast generation and immunoglobulin secretion from normal but not CD25-deficient cells; these results demonstrate that IL-21 sensitizes B cells to the stimulatory effects of IL-2 via STAT3
JAK3 but not JAK1 is constitutively phosphorylated in mycosis fungoides and its leukaemic variant Sezary syndrome [85, 86]. These results suggest that the lack of JAK1 phosphorylation and the constitutive activation of JAK3 might be characteristics of an IL-2 receptor (IL-2R)-expressing transformed cell; it is possible to speculate that the JAK3 kinase may be “more important” in IL-2 signalling than JAK1 [64] (Figure 1(b))
Summary
Interleukin 2 (IL-2) is a 15.5 kDa cytokine that is primarily produced by CD4+ T cells following antigen stimulation [1] and to a lesser extent by CD8+ cells [2], NK T cells [3], mast cells [4], monocytes [5], and myeloid dendritic cells (mDCs) [5, 6]. IL-2 promotes regulatory T cell development and constrains Th17 cell polarization [7,8,9] To elicit these biological effects, IL-2 sends signals through the IL2 receptor (IL-2R) complex. Subsequent tyrosine phosphorylation of the IL-2Rβ chain provides docking sites for effector molecules, including signal transducer and activator of transcription (STAT) 5a and STAT5b, via their Src homology 2 domains [12]. IL-2Rβ propagates signals following receptor-ligand engagement, thereby controlling the recruitment and activation of effector proteins, and is known to be phosphorylated on its tyrosine; this modification of the β chain has been studied extensively. Mediators of Inflammation of Akt, ERK1/2, and transcriptionally active STAT5 These results provide the first evidence of the identification and functional characterization of threonine phosphorylation of an interleukin receptor. These secreted proteins can either compete with membrane cytokine receptors for ligand binding or sequester the cognate cytokine, thereby limiting its bioavailability [17]
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