Biological functions of IL-4/IL-13, signaling cascades and implication in growth and development of tumor

Abstract

Interleukin-4 and 13 are immunoregulatory cytokines secreted mainly by activated Th2 cells. They regulate multiple biological functions such as proliferation, differentiation and apoptosis in various cell types of hematopoietic and non-hematopoietic origin. Both cytokines are critical to the differentiation of Th0 cells into Th2 cells and simultaneous suppression of Th1 type T cell-mediated immunity thus involved in the amplification of Th2 type of immune responses. Acting on the every immune cell population through their cell surface receptors, they are able to subdue the antitumor function of immunopotent cells and tumor immunosurveillance mechanism(s), and therefore favor unrestricted growth and progression of tumor. Both cytokines have shared biological effects due to common receptor subunits. They have both type I and type II receptor complexes forming at least four receptor complexes viz IL-4Rα-γc, IL-4Rα-IL-13Rα1, IL-4Rα-IL-13Ra2, IL-13Ra2 expressed in many tumor cell types. IL-4 and IL-13 mediate signal through two different pathways IL-4-IRS pathway involving insulin receptor substrate molecules leading to the activation of MAPK and PKC and JAK-STAT pathway resulting in the activation of STAT6. MAPK and PKC activated in response to IL-4 and IL-13 leads to tumor cell growth and survival by activating proliferation and anti-apoptotic mechanism(s), while STAT6 activation leads to the expression of CD23, MHC class II, germ line immunoglobulin ε, CD45, SOCS etc. In addition, signaling through IL-13Ra1 leads to activation of several STAT molecules including STAT1α, 3, 5α, 5β and STAT6, all results in the proliferation of tumor cells and differentiation of Th2 cells. IL-13Rα2, previously known as decoy receptor, also transduce signal and leads to the activation of ERK and p38 MAPK which regulate proliferation and metastasis of tumor cells. The signaling cascades induced by IL-4 and IL-13 are modulated by many adaptor and regulatory molecules, which are also known to be associated with many hematological and non-hematological malignancies and therefore they could be an attractive target to develop a therapeutic agent for the treatment of cancer. © 2013 by Nova Science Publishers, Inc. All rights reserved.