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. The cell that initially produces IL-4, thus inducing Th2 differentiation, has not been identified, but recent studies suggest that basophils may be the effector cell. It is closely related and has functions similar to interleukin 13.
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.
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.
IL-4 plays an important role in the development of certain immune disorders, particularly allergies and some autoimmune diseases.
Allergic diseases
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 VCAM-1 molecules, 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 a significant effect on tumor progression. Increased IL-4 production was found in breast, prostate, lung, renal cells and other types of cancer. Many overexpression of IL-4R has been found in many types of cancer. Renal cells and glioblastoma modify 10,000-13,000 receptors per cell depending on tumor type. IL-4 can primitively motivate tumor cells and increase their apoptosis resistance by increasing tumor growth.
Nervous system
Brain tissue tumors such as astrocytoma, glioblastoma, meningioma, and medulloblastoma overexpress receptors for various growth factors including epidermal growth factor receptor, FGFR-1, IL-13R. Most human meningiomas massively expresses IL-4 receptors, indicating its role in cancer progression. They express IL-4Rα and IL13Rα-1-1, but not the surface γc chain, suggesting that most human meningiomas express IL-4 type II.
HIV
IL-4 may also play a role in the infection and development of HIV disease. Auxiliary T-lymphocytes are a key element of HIV-1 infection. Several signs of immune dysregulation such as polyclonal B-cell initialization, previous cell-mediated antigen-induced response and hypergammaglobulinaemia occur in most HIV-1 infected patients and are associated with cytokines synthesized by Th2 cells. Increased IL-4 production by Th2 cells has been demonstrated in people infected with HIV.
