In the pathway, NF-κB/Rel proteins are bound and inhibited by IκB proteins. Growth factors, proinflammatory cytokines, chemotherapy, radiotherapy, and antigen receptors activate an IKK complex, which phosphorylates IκB proteins. Phosphorylation of IκB leads to its ubiquitination and proteasomal degradation, freeing NF-κB/Rel complexes. The transcription factor NF-κB is thereby released and promotes the expression of cytokines, cell adhesion molecules, and antiapoptotic proteins. The NF-κB signal transduction pathway in development and dysfunction of the immune system. In NF-κB pathway, most proteins regulate the expression of genes influencing a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis.
Nuclear factor kappa B is a dimer belonging to Rel family, that contains a highly conserved Rel-homology domain (RHD). The NFκB proteins have five different monomers that share a Rel homology domain in their N-terminus. The p105 and p100 which precursors of NFκB1 and NFκB2 that are transformed to mature NFκB subunits (p50 and p52) by the ubiquitin pathway. The nuclear translocation of NFκB, inhibitory kappa B (IκB) proteins, and DNA binding interaction with RHD.
NFκB signalling pathway have two major ways,that as : (1) the canonical (mediated by IκB degradation), and (2) the non-canonical (p100 mediated) pathways. In the cell ,the NFκB dimers are attached to IκB proteins under normal conditions. The canonical pathway will be activated by the inflammatory reaction, for example,interleukins, TNF-α, or LPS, that leads to the activation of the IκB kinase (IKK) complex. Then NFκB becomes free, which follows it moves to the nucleus and initiates transcription of the target genes.
Interleukins are a group of cytokines that were first seen to be expressed by leukocytes. The term interleukin describes a variety of polypeptides that act specifically as mediators between leucocytes. However, the name interleukin is something of a relic, since it has been found that interleukins are produced by a wide variety of body cells. The majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through monocytes, macrophages, and endothelial cells. The function of the immune system depends in a large part on interleukins. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Rare deficiencies of a number of Interleukins have been described, all featuring autoimmune diseases or immune deficiency. Learn more about what are interleukins.
The majority of interleukin cytokines can be divided into specific families based on structure and function. The 3-dimensional structure of the mature forms of each member of the human interleukin-1 superfamily is composed of 12-14 β-strands producing a barrel-shaped protein. The cytokines of interleukin-1 superfamily are key molecules both in the innate and in the adaptive immune response. Inclusion in the interleukin-6 family is based on a helical cytokine structure, shared receptor subunit makeup and activation of the signal transducing receptor protein glycoprotein 130 (gp130). Interleukin-10 is the prototypic member of the interleukin-10 cytokine family, which also include IL-19, IL-20, IL-22, IL-24 and IL-26.The interleukin-12 family cytokines, including IL-12, IL-23, IL-27 and IL-35, are key players in the regulation of T cell responses. All members of the interleukin-17 family have a similar protein structure, with four highly conserved cysteine residues critical to their 3-dimensional shape. There are still other interleukin molecules, which are currently not included in a defined family, such as, IL-13, IL-16, IL-32, IL-34, etc.
The Interleukin-1 superfamily & Interleukin-1 receptor family plays critical roles in initiating and promoting the host response to injury or infection, including fever, sleep, acute phase protein synthesis, chemokine production, adhesion molecule up-regulation and production and release of matrix metalloproteinases and growth factors. The original members of the Interleukin-1 superfamily are IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1RA). Six additional members of this family have since been described: IL-1F5, IL-1F6, IL-1F7, IL-1F8, IL-1F9, IL-1F10, with structural homology to IL-1α, IL-1β or IL-1RA. Another molecule described as a member of Interleukin-1 superfamily is IL-18. Recently, a further putative member of the Interleukin-1 superfamily has been described that is called IL-33.
Interleukin-6 family of cytokines includes IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine (CLC) and cardiotrophin-1 (CT-1). Members of the interleukin-6 family cytokines utilize one or both of the shared receptor signal transducing subunits, gp130 and LIF receptor (LIFR). Interleukin-6 family cytokines binding of gp130 activates the JAK/STAT signaling pathway, which functions in many biological processes. Interleukin-6 and their receptor have been implicated in prostate cancer progression.
Interleukin-10, also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. IL-10 shares use of IL-10 receptor 2 (IL-10R2) in cell signaling with other members of this family (L-22, IL-26) and interferon-like molecules (limitin, L-28A, IL-28B, IL-29). The interleukin-10 family, interferons and interferon-like molecules constitute the Class 2 alpha-helical cytokines, which initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms.
The interleukin-12 family cytokines are key players in the regulation of T cell responses. Interleukin-12 has long been appreciated to play central role in the generation of TH1 cells. Subsequent studies indicated that two closely related interleukins, IL-23 and IL-27, also regulate TH1-cell responses. IL-35, a novel member of interleukin-12 family, is secreted by regulatory T cells, and suppresses inflammatory responses of immune cells. Function of the interleukin-12 family members largely depend on interleukin -12 family receptors.
Cytokines of the interleukin-17 family include IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F. Interleukin-17 family members have been reported to function in numerous immune processes. Most notably, IL-17 is involved in inducing and mediating proinflammatory responses. This proinflammatory activity is exemplified by their involvement in pulmonary inflammatory responses. Both IL-17A and IL-17F are involved in the recruitment of neutrophils, and IL-17E is able to induce Th2 cytokine production and eosinophilia. Cytokines of interleukin-17 family are all well conserved in mammals, with as much as 62–88% of amino acids conserved between the human and mouse homologs.