Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes

Abstract

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.

Revisiting the Interaction of γδ T-Cells and B-Cells

“…IL-4 can be produced by CD4 + T, γδ T, NKT, B-cells, basophils, eosinophils, mast cells, and also by type-2 innate lymphoid cells. In mice, IL-4 induces the differentiation of naïve CD4 + T-cells into Th2 cells, drives the Ig class switch to IgG1 and IgE in B-cells, and induces alternative macrophage activation [44]. IL-4 can also induce Ig class switching toward the expression of IgG4 and IgE in humans [45,46].…”

Regulation of IgE by T follicular helper cells

“…IL‐4‐bound type I receptor complex results in both STAT6 activation, which is critical for IgE induction, and PI3K signaling, which negatively regulates IgE induction . As IL‐13‐bound type II receptor complex exclusively activates STAT6 and is also more stable ( K d = 20 nM) than the IL‐4 bound type I ( K d = 559 nM) or type II ( K d = 487 nM) complexes, IL‐13 may lead to more sustained STAT6 activation and promote IgE production …”

“…[93][94][95] As IL-13-bound type II receptor complex exclusively activates STAT6 and is also more stable (K d = 20 nM) than the IL-4 bound type I (K d = 559 nM) or type II (K d = 487 nM) complexes, IL-13 may lead to more sustained STAT6 activation and promote IgE production. 93,96,97…”

Virus-Like Particle-Mediated Vaccination against Interleukin-13 May Harbour General Anti-Allergic Potential beyond Atopic Dermatitis

“…The present review will discuss these four themes in turn, not aiming to be exhaustive, but rather with the intent to stimulate further efforts to tackle many open questions. By implication, therefore, this review does not intend to deliver a broader review of the signalling, structure, or immunobiology of IL-13 which have been reviewed excellently recently elsewhere [1][2][3].…”