IL-2 signaling pathways and regulation
The pleiotropic effects of IL-2 are enabled due to the fact that IL-2 signal can be transduced via 3 different signaling pathways; JAK-STAT, PI3K/Akt/mTOR and MAPK/ERK pathway. After IL-2 binding to its receptor, cytoplasmatic domains of CD122 and CD132 heterodimerize. This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors, predominantly STAT5, which dimerize and migrate to the cell nucleus where they bind to DNA.Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints is signaling through TCR, antigen receptor of T-lymphocytes after recognizing MHC-peptide complex. Signaling pathway from TCR then goes through phospholipase-C (PLC) dependent pathway. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. After costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced. At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation. NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus. AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct.
NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter.
Function
IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD). IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4+ T cell differentiation into Th1 and Th2 lymphocytes while it impedes differentiation into Th17 and folicular Th lymphocytes.IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells.Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity. Role in disease
While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis. Medical use
Pharmaceutical analogues
Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin.