Interleukin 4
The interleukin 4 is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.
Function
Interleukin 4 has many biological roles, including the stimulation of activated B cell and T cell proliferation, and the differentiation of B cells into plasma cells. It is a key regulator in humoral and adaptive immunity. IL-4 induces B cell class switching to IgE, and up-regulates MHC class II production. IL-4 decreases the production of Th1 cells, macrophages, IFNγ, and dendritic cells IL-12.Overproduction of IL-4 is associated with allergies.
Inflammation and wound repair
play an important role in chronic inflammation and wound repair. The presence of IL-4 in extravascular tissues promotes alternative activation of macrophages into M2 cells and inhibits classical activation of macrophages into M1 cells. An increase in repair macrophages is coupled with secretion of IL-10 and TGF-β that result in a diminution of pathological inflammation. Release of arginase, proline, polyaminases and TGF-β by the activated M2 cell is tied with wound repair and fibrosis.Receptor
The receptor for interleukin-4 is known as the IL-4Rα. This receptor exists in 3 different complexes throughout the body. Type 1 receptors are composed of the IL-4Rα subunit with a common γ chain and specifically bind IL-4. Type 2 receptors consist of an IL-4Rα subunit bound to a different subunit known as IL-13Rα1. These type 2 receptors have the ability to bind both IL-4 and IL-13, two cytokines with closely related biological functions.Structure
IL-4 has a compact, globular fold, stabilised by 3 disulphide bonds. One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist. The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet.Evolution
IL-4 is closely related to IL-13, and both stimulate type 2 immunity. Genes of this family have also been found in fish, both in bony fish and cartilaginous fish; because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13.Discovery
This cytokine was co-discovered by Maureen Howard and William E. Paul as well as by Ellen Vitetta and her research group in 1982.The nucleotide sequence for human IL-4 was isolated four years later confirming its similarity to a mouse protein called B cell stimulatory factor-1.
Animal studies
IL-4 has been found to mediate a crosstalk between the neural stem cells and neurons that undergo neurodegeneration, and initiate a regeneration cascade through phosphorylation of its intracellular effector STAT6 in an experimental Alzheimer's disease model in adult zebrafish brain.Clinical significance
IL-4 plays an important role in the development of certain immune disorders, particularly allergies and some autoimmune diseases.Allergic diseases
IL-4, along with other Th2 cytokines, is involved in the airway inflammation observed in the lungs of patients with allergic asthma.Allergic diseases are sets of disorders that are manifested by a disproportionate response of the immune system to the allergen and Th2 responses. These pathologies include, for example, atopic dermatitis, asthma, or systemic anaphylaxis. Interleukin 4 mediates important pro-inflammatory functions in asthma, including induction of isotype rearrangement of IgE, expression of vascular cell adhesion molecule 1, promoting eosinophilic transmigration through endothelium, mucus secretion and T helper type 2 leading to cytokine release. Asthma is a complex genetic disorder that has been associated with IL-4 gene promoter polymorphism and proteins involved in IL-4 signaling.
Tumors
IL-4 has been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.IL-4 has a significant effect on tumor progression. Increased IL-4 production was found in breast, prostate, lung, renal cells and other types of cancer. Overexpression of IL-4R has been found in many types of cancer. Renal cells and glioblastoma modify - receptors per cell depending on tumor type.
IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.