CYTOKINE PANEL 1 (RAT) (IFN-γ, IL-1β, IL-2, IL-6, IL-10, KC, TNFα)
IFN-γ – Interferon-gamma (IFNγ), exerts a wide range of immunoregulatory activities Mature mouse IFN-gamma exists as a noncovalently linked homodimer of 20-25 kDa variably glycosylated subunits. IFNγ binds IFN-γ receptors (IFNγ R1 and IFNγ R2), which are expressed on most immune cells, to activate the JAK-STAT pathway. IFNγinduced signaling increases the expression of class 1 major histocompatibility complex (MHC) molecules. IFNγ is produced by a variety of immune cells under inflammatory conditions, notably by T cells and NK cells. It plays a key role in host defense by promoting the development and activation of Th1 cells, chemoattraction and activation of monocytes and macrophages, and up-regulation of antigen presentation molecules. It also exhibits antiviral, antiproliferative, and apoptotic effects.
IL-1β – The IL-1 family consists primarily of three proteins: IL-1α, IL-1β (agonists) and IL-1ra (antagonist) which interact with the IL-1 receptor. IL-1β shares 33% homology with IL-1α. IL-1β exists as a 33 kDa precursor which is cleaved by caspase-1 into its 17 kDA active form. It is unknown how IL-1β is actively secreted but it is suggested exocytosis, transport by multi-drug resistance transporters, and cell death may all play a role. Knockout models of IL-1β show no gross physiological detriment, though its role is suspected to function in disease states rather than healthy tissue. Evidence shows potential involvement in Long Term Potentiation demonstrating increases following induction, and the prevention of induction with a competitive antagonist. IL-1β is believed to be part of an inflammatory response thought to be protective to insult and injury but often goes awry. There is a distinguishable link between oxidative stress, glutamate excitotoxicity and IL-1β.
Interleukin 2 (IL-2) is an alpha-helical cytokine of 153 amino acids (molecular weight 17.6kDa) whose primary role is regulation of activities of lymphocytes that are responsible for immunity. During infection, the binding of antigens to T cell receptors trigger secretion of IL-2 and expression of IL-2 receptors (IL-2R), promoting the growth, proliferation, and differentiation of T cells to become effector T cells. IL2/IL2R interaction stimulates growth and differentiation of antigen-specific CD4+ and CD8+ T cells, resulting in immunologic memory of the antigens. IL-2 is also responsible for discrimination between foreign (“non-self”) and “self”, and as such is a target of immunosuppressive regimens which inhibit the production of IL-2 by antigen-activated T cells and block IL-2R signaling, preventing the clonal expansion and function of antigen-selected T cells.
Interleukin 6 (IL-6) is an alpha-helical cytokine with a wide variety of biological functions, including inducement of acute phase reactions, inflammation, hematopoiesis, bone metabolism, and cancer progression. It is secreted by multiple cell types as a 22k-28k dalton phosphorylated and variably glycosylated molecule. Mature human IL-6 is 183 amino acids (aa) in length and shares 41% aa sequence identity with mouse and rat IL-6. IL-6 is secreted by T cells and macrophages to induce immune responses following tissue trauma leading to inflammation. IL-6 also acts as an anti-inflammatory myokine, secreted by muscles during contraction after which it acts to increase breakdown of fats and improve insulin resistance. Because of its role in inducing inflammation and auto-immune response, there is interest in developing anti-IL-6 agents as potential therapies against various diseases, including rheumatoid arthritis and cancer.
Interleukin 10 (IL-10) is an alpha-helical, homodimeric cytokine, each subunit composed of 178 amino acids (18 kDa). The major role of IL-10 is to act as an antiinflammatory cytokine. It is produced primarily by monocytes, type 2 T helper cells and B cells. IL-10 is also released by cytotoxic T cells to inhibit the action of natural killer cells during the immune response to viral infection. It has multiple effects in immunoregulation and inflammation, including down regulation of Th1 cytokine expression, MHC class II antigens, and stimulatory molecules on macrophages. IL-10 can also inhibit synthesis of pro-inflammatory cytokines such as IFN-g, IL-2, TNFa and GM-CSF made by macrophages and regulatory T cells. IL-10 is among cytokines secreted by muscle cells, whose elevation during physical activity suggests that exercise promotes an environment of anti-inflammatory cytokines. IL-10 has garnered interest as a potential anti-inflammatory therapeutic, but initial studies with rheumatoid arthritis have shown limited efficacy.
KC, better known as chemokine (C-X-C motif) ligand 1 (CXCL1), is a small cytokine that belongs to the CXC chemokine family. It is expressed by macrophages, neutrophils, and epithelial cells and secreted by human melanoma cells. CXCL1 plays a role in spinal cord development by inhibiting the migration of oligodendrocyte precursors and is involved in the processes of angiogenesis, arteriogenesis, inflammation, wound healing, and tumorigenesis. Dysregulation of CXCL1 has shown to be correlated with tumors, lung infections, pulmonary diseases and more.
Tumor Necrosis Factor alpha (TNFα) is a polypeptide cytokine produced by monocytes and macrophages. The involvement of TNFα in several signal transduction pathways links the protein to such diverse functions as acute inflammation, apoptosis, septic shock, cellular proliferation, and differentiation. The clinical relevance of TNFα is from its association with numerous disease states including rheumatoid arthritis, cancer, cachexia, and Crohn’s disease.