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Interleukin 4 (IL-4)

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Interleukin 4 (IL-4) is also known as B-cell stimulatory factor 1. IL-4 is a pleiotropic anti-inflammatory cytokine that is secreted primarily by mast cells, Th2 cells, eosinophils and basophils. Recent studies also indicate that IL-4 enhances Th2 immunity by inhibiting Th1 responses through suppression of IL-12 signaling. In addition to playing an important role in modulating the activities of the immune system, research indicates that it also plays a critical role in higher functions of the normal brain, such as memory and learning (although the precise mechanisms are not well-understood). Levels of IL-4 are typically low in the blood of healthy people, so measuring this cytokine in serum or plasma may require an ultra-sensitive assay.

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Name: Interleukin 4 (IL-4)
Category: Health & Inflammation
Type of test: Blood 

IL-4, also known as B-cell stimulatory factor 1, is an anti-inflammatory cytokine very similar in both structure and function to IL-13. So similar, in fact, that the type 2 IL-4 receptor consisting of an IL-4Ra subunit and an IL-13Ra1 subunit does not distinguish between the two. Like many other cytokines, IL-4 is small and folds into a globular structure stabilized by disulfide bonds, with its primary targets being Th1 and B cells. The cell types responsible for the secretion of the majority of circulating IL-4 are mast cells, Th2 cells, eosinophils and basophils. IL-4 is involved in several processes associated with immunity, but it also serves important functions in tissue repair and even learning and memory, with dysregulation being linked with several pathological conditions. IL-4 overexpression is also found within numerous cancerous tumors, including those of the breast, prostate, lungs, and kidneys. However, other research finds that IL-4 is a potent anti-tumorigenic agent in mice. The general consensus is that the amount, origin, location, and relative receptor density for IL-4 are all influence whether this cytokine has pro- or antitumor effects.

IL-4 also plays an important role in the etiology of allergic diseases. In studies looking at the role of IL-4 in excessive IgE responses to allergens, elevated levels of IL-4 positively correlate with the severity of the response. Furthermore, IL-4 deficient mice have been shown to be less prone to airway inflammation within the presence of an allergen when compared to wild type mice. In addition to regulating allergic responses, the activities of IL-4 also have implications for the course of infectious diseases. For example, research finds that mice expressing high levels of IL-4 are less able to fight off infections from pathogens like Leishmania major, an intracellular parasite. Moreover, mice predisposed to overexpress IL-4 become more immunocompetent upon administration of anti-IL4 antibodies. Together, these findings suggest a complex role for IL-4 in the regulation immune responses to allergens and infectious illnesses, effects mediated primarily through interactions with T cells. 

Within the context of learning and memory, IL-4 has shown to be important even within a healthy human brain, likely through the modulatory activity it exerts on T cell activity and inflammation. Additionally, psychological stress reduces IL-4 secretion in the brain, lending to a more inflammatory cytokine profile, presenting a potential pathway through which stress negatively impacts brain health. Currently, levels of IL-4 can only be measured in serum / plasma samples.

Del Prete, G., Maggi, E., Parronchi, P., Chretien, I., Tiri, A., Macchia, D., ... & Romagnani, S. (1988). IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. The Journal of Immunology140, 4193-4198. https://www.jimmunol.org/content/140/12/4193/tab-article-info

Finkelman, F. D., Katona, I. M., Urban, J. F., Holmes, J., Ohara, J., Tung, A. S., ... & Paul, W. E. (1988). IL-4 is required to generate and sustain in vivo IgE responses. The Journal of Immunology141, 2335-2341. https://www.jimmunol.org/content/141/7/2335/tab-article-info

Gadani, S.P., Cronk, J. C., Norris, G. T., & Kipnis, J (2012). IL-4 in the brain: a cytokine to remember. Journal of Immunology, 189, 4213-4219. (link)

Noben-Trauth, N., Kropf, P., & Müller, I. (1996). Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science271, 987-990. https://pubmed.ncbi.nlm.nih.gov/8584936/

Setrerrahmane, S. & Xu, H. (2017). Tumor-related interleukins: old validated targets for new anti-cancer drug development. Molecular Cancer, 16, e153. (link

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