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Interleukin-35 is a glycosylated, disulfide-linked, heterodimeric protein comprised of the p35 subunit of IL-12 (IL-12 alpha) and the beta subunit of IL-27 (EBI3). IL35 is expressed by regulatory T-cells (Tregs), macrophages and some trophoblast and dendritic cells. IL-35 is produced in response to inflammation and generally serves as an inflammation suppressor. Interleukin-35 curbs inflammation by applying multiple activities, including the stimulation of regulatory T-cells and the inhibition of Th17 cells.

The Defensin family are highly similar in their protein sequence and are microbicidal & cytotoxic peptides made by neutrophils. Beta Defensin-1 is an antimicrobial peptide having the resistance of epithelial surfaces to microbial colonization. Beta Defensin-1 has close proximity to Defensin Alpha-1 and has been implicated in the pathogenesis of cystic fibrosis.
Skin of patients having atopic dermatitis patients and mycosis fungoides (non-lesional and lesional) show lower human Beta Defensin-1 mRNA expression and higher human Beta Defensin-2 and human Beta Defensin-3 mRNA expression.
Beta Defensin is highly expressed by epithelial cells.
Beta-defensin 1 may play a role in the pathogenesis of severe sepsis.

NGF-beta has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with allergic rhinitis.

This gene is a member of a family of neurotrophic factors, neurotrophins that control survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and less influenced by environmental signals. While knock-outs of other neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 prove lethal during early postnatal development, NTF5-deficient mice only show minor cellular deficits and develop normally to adulthood.

Resistin, a product of the RSTN gene, is a peptide hormone belonging to the class of cysteine-rich secreted proteins which is termed the RELM family, and is also described as ADSF (Adipose Tissue- Specific Secretory Factor) and FIZZ3 (Found in Inflammatory Zone). Human resistin contains 108 amino acids as a prepeptide, and its hydrofobic signal peptide is cleaved before its secretion. Resistin circulates in human blood as a dimeric protein consisting of two 92 amino acid polypeptides, which are disulfide-linked via Cys26.
Resistin may be an important link between obesity resistance. Mouse resistin, specifically produced and secreted by adipocyte, acts on skeletal muscle myocytes, hepatocytes and adipocytes themselves so that it reduces their sensitivity. They have also suggested that resistin is present at elevated levels in blood of obese mice, and is down regulated by fasting and antidiabetic drugs. Way et al., on the other hand, have found that resistin expression is severly suppressed in obesity and is stimulated by several antidiabetic drugs.
Other studies have shown that mouse resistin increases during the differentiation of adipocytes, but it also seems to inhibit adipogenesis. In contrast, the human adipogenic differentiation is likely to be associated with a down regulation of resistin gene expression.

Hypoxia-inducible factor-1 (HIF-1), identified as one of the transcription factors, has been found to play an essential role in cellular and systemic oxygen homeostasis. HIF-1 is a heterodimer composed of HIF-1b subunit and one of three subunits (Hif-1a, Hif-2 (or Hif-3)). The activation of Hif-1 (is closely associated with a variety of tumors and oncogenic pathways. Hif-1 (consists of DNA binding domain (DBD domain), Dimerization domain and C-terminal regulatory domains, including two transactivation domains (TAD), an oxygen-dependent degradation (ODD) domain, and inhibitory domains. Under hypoxic conditions HIF1A activates the transcription of more than 40 genes, including, erythropoietin, glucose transporters, glycolytic enzymes, VEGF, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1A also plays a crucial role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. It binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation involves recruitment of transcriptional coactivators such as CREBPB and EP300. Its activity is improved by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX appears to activate CTAD and potentiates activation by NCOA1 and CREBBP. The induction is under reduced oxygen tension. HIF1A is also induced by a variety of receptor-mediated factors such as growth factors, cytokines, and circulatory factors for example PDGF, EGF, FGF-2, IGF-2, TGF-1 beta, HGF, TNF alpha, IL-1 beta, angiotensin-2 and thrombin. Nevertheless, this induction is less intense than that stimulated by hypoxia.

Adiponectin is a hormone exclusively expressed from adipose tissue. Many studies demonstrate that adiponectin has direct anti-diabetic, anti-atherogenic and anti-inflammatory functions. APM-1 can increase insulin sensitivity of skeletal muscle, attenuate hepatic lipogenesis and luconeogenesis, regulate NO production in endothelial cells, inhibit proliferation of smooth muscle cells and prevent lipid accumulation of macrophage cells.
In the circulation, adiponectin is present as three different oligomeric complexes, including the high molecular weight (HMW), the middle molecular weight (MMW, also called hexamer) and low molecular weigh (MMW, also called trimer) forms 8. Different oligomeric complex of adiponectin activates different signaling pathways and exerts distinct functions.

EBI3 has an induced expression in B lymphocytes in reaction to Epstein-Barr virus infection. EBI3 encodes a secreted glycoprotein belonging to the hematopoietin receptor family, and heterodimerizes with a 28 kDa protein to form iIL-27. EBI3 drives rapid clonal expansion of naive cd4(+) t-cells. EBI3 strongly synergizes with IL-12 to activate IFN-gamma production of naive cd4(+) t-cells. EBI3 mediates its biologic effects through the cytokine receptor wsx-1/tccr.

IL13 is an immunoregulatory cytokine produced primarily by activated Th2 cells. IL-13 is involved in several stages of B-cell maturation and differentiation. It up-regulates CD23 and MHC class II expression, and promotes IgE isotype switching of B cells. This cytokine down-regulates macrophage activity, thereby inhibits the production of pro-inflammatory cytokines and chemokines. This cytokine is found to be critical to the pathogenesis of allergen-induced asthma but operates through mechanisms independent of IgE and eosinophils. This gene, IL3, IL5, IL4, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL4.

The IL1RL1 gene is a member of the IL-1 receptor family, encoding a transmembrane protein with a structure similar to IL-1R1. IL1RL1 is a receptor for interleukin-33, its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. IL1RL1 may possibly be involved in helper T-cell function. IL1RL1 is highly expressed in kidney, lung, placenta, stomach, skeletal muscle, colon and small intestine.
A soluble form of the IL1RL1 is produced from the same gene by alternative splicing and was shown to be expressed in several cell types including fibroblasts and mast cells. Soluble IL1RL1 also acts as a negative regulator of Th2 cytokine production and high levels have been reported in several disease states and conditions including asthma, sepsis and myocardial infarction.
Analysis of the similar gene in mouse suggested that the IL1RL1 receptor can be induced by proinflammatory stimuli, and may be involved in the function of helper T cells.

Human IL-36a belongs to the IL-1 family which includes IL-1b, IL-1a, IL-1ra, IL-18, IL-36ra (IL1F5), IL-36b (IL1F8), IL-36g (IL1F9), IL-37 (IL1F7) and IL-38 (IL-1F10). The IL-1 family members display a 12 b-strand, b-trefoil configuration, and are thought to have ascended from a mutual ancestral gene. IL-36a is an 18-22kDa, 158aa intracellular and secreted protein which holds no signal sequence, no prosegment and no potential from N-linked glycosylation sites. IL-36a is released as a reaction to LPS and the cell ATP-induced activation of the P2X7 receptor.
Human IL-36a (aa 6-158) shares 57-68% aa sequence homology with mouse, rabbit, equine and bovine IL-36a and 27-57% aa sequence homology with other new IL-1 family members. IL-36a is mostly found in skin and lymphoid tissues, but also in fetal brain, trachea, stomach and intestine.

Mouse IL-36b belongs to the IL-1 family that includes IL-1b, IL-1a, IL-1ra, IL-18, IL-36ra (IL1F5), IL-36b (IL1F8), IL-36g (IL1F9), IL-37 (IL1F7) and IL-38 (IL-1F10). The IL-1 family members display a 12 b-strand, b-trefoil configuration, and are thought to have ascended from a mutual ancestral gene. Mouse IL-36b/IL-1F8 is a 183 amino acid protein which holds no signal sequence, no prosegment and no potential N-linked glycosylation site(s). Mouse IL-36b like its human homologue is actively secreted. Mouse IL-36?/IL-1F8 shares 61-74% aa homology with human IL-36?/IL-1F8 isoform 2 and rat IL-1F8.

IL-36gamma belongs to the IL-1 family which includes IL-1b, IL-1a, IL-1ra, IL-18, IL-36 Ra (IL-1F5), IL-36a (IL-1F6), IL-36b (IL-1F8), IL-37 (IL-1F7) and IL-1F10. ). The IL-1 family members display a 12 b-strand, b-trefoil configuration, and are thought to have ascended from a mutual ancestral gene. IL-36g is an 18-22 kDa, 169aa intracellular and secreted protein which holds no signal sequence, no prosegment and no potential N-linked glycosylation sites. Human IL-36g shares 58%- 69% aa sequence homology with mouse, rat, bovine and equine IL-36g, and 23 - 57% aa sequence homology with other family members. The IL-36g receptor is a mixture of IL-1 Rrp2, mostly located in epithelia and keratinocytes, and the extensively expressed IL-1 RAcP. All IL-36 (a, b and g) activate N F-?B and MAPK pathways in an IL-1 Rrp2 dependent reaction. Additionally, IL-36g induces production of inflammatory cytokines and chemokines like CXCL8/IL-8.

IL-7 is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. This cytokine is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival.

Eukaryotic Translation Initiation Factor 3F, also known as EIF3F belongs to the eIF-3 subunit F family. EIF3F is a component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which isessential for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosomeand facilitates the recruitment of eIF-1, eIF-1A, eIF 2: GTP: methionyl-tRNAi and eIF-5 to form the 43S preinitiationcomplex (43S PIC). In addition, the eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA forAUG recognition. The eIF-3 complex is also necessary for disassembly and recycling of post termination ribosomalcomplexes and subsequently prevents premature union of the 40S and 60S ribosomal subunits prior to initiation. Among the diseases associated with EIF3F are intrahepatic cholangiocarcinoma, and cholangiocarcinoma.

Human IL-17A/F is a 40kDa glycoprotein which is secreted as a disulfide-linked heterodimer. IL-17A/F consists of two proteins of the IL-17 family, IL-17A and IL17F. Proteins of the 6 homodimeric IL17 family show a cysteine knot motif that contains two disulfide-bonds. Human IL17A is produced as a 155 a.a precursor that includes a 23 amino acids signal sequence and a 132 amino acid chain that includes an N-linked glycosylation site. Human IL17F is produced as a 153 amino acid precursor with a 20 amino acid signal sequence and a 133 amino acid region. Similar to IL17A, IL17F also has an N-linked glycosylation site. Both proteins (IL17A & IL17F) share 50% amino acid sequence identity. Human IL17A & IL17F show approximately 60% homology in their amino acid sequence to mouse IL-17A and IL-17F. Interleukin-17A/F and IL17A, IL17F homodimers are manufactured by activted CD4+ T cells, called Th17. IL-23 causes Th17 lymphocytes to manufacture IL-17A/F. IL17RA and IL17RC form a heterodimer for the binding of IL17A and IL17F. IL-17A/F binds IL-17RA. Interleukin-17A/F induces chemokine production and airway neutrophilia with intermediate potency between IL17A (most potent) and IL17F (least potent).

IFN regulatory factor 2 is a member of the IFN regulatory transcription factor (IRF) family. IRF2 competitively inhibits the IRF1-mediated transcriptional activation of IFNs alpha and beta, and presumably other genes that employ IRF1 for transcription activation. However, IRF2 also functions as a transcriptional activator of histone H4. IRF2 binds to the upstream regulatory region of type-1 IFN and IFN-inducible MHC class-1 genes (the IFN consensus sequence (ics) and represses those genes.

EIF2S1 participates in the premature steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA which binds to a 40S ribosomal subunit, followed by mRNA binding to create a 43S pre-initiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 should exchange with GTP by way of a reaction catalyzed by eIF-2B.

TGFB-Induced Factor Homeobox 2-Like Y-Linked (TGIF2LY) is a part of the TALE/TGIF homeobox family of transcription factors. TGIF2LY is located in the male specific region of chromosome Y, in a block of sequence which is the outcome of a large X-to-Y transposition. TGIF2LY act as a regulator of TGIF2LX due to the fact that the C-terminus of TGIF2LY is different from that of its chromosome X homolog (TGIF2LX). TGIF2LY has also a transcription role in testis.

GDNF Family Receptor Alpha 3 (GFRA3) belongs to the GDNF receptor family. GFRA3 creates a signaling receptor complex with RET tyrosine kinase receptor and binds the ligand, artemin (ARTN).

SAA1 protein is an acute phase apolipoprotein reactant which is produced mostly by hepatocytes and under regulation of inflammatory cytokines. SAA1 (Serum amyloid A1) protein is produced mainly in the liver and circulates in low levels in the blood. The SAA1 seems to have a role in the immune system. SAA1 protein levels increase in the blood and other tissues under conditions of inflammation. SAA1 may facilitate the repair of injured tissues; it also acts as an antibacterial agent, and signals the migration of germ-fighting cells to sites of infection. SAA1 also functions as an apolipoprotein of the HDL complex.
Elevated levels of SAA1 ultimately affect secondary amyloidosis, extracellular amassing of amyloid fibrils, resulting from a circulating precursor, in a variety of tissues and organs. The most widespread type of amyloidosis appears secondary to chronic inflammatory disease, mainly rheumatoid arthritis. The SAA1 cleavage product a designated amyloid protein A is deposited systemically as amyloid in vital organs such as the liver, spleen, and kidneys in chronic inflammatory diseases patients. These deposits are extremely insoluble and resistant to proteolysis; they disrupt tissue structure and compromise performance.

Interleukin-1 alpha is a proinflammatory cytokine produced by a wide variety of cell types, including macrophages, osteoblasts, monocytes and hepatocytes. Circulating levels of are normally low and only rise after stimulation by agents such as those produced byinflammation, infection or microbial endotoxins. IL-1 alpha possesses a wide variety of biological activities and exerts its effects by binding to specific cell surface receptors.

The Defensin family are highly similar in their protein sequence and are microbicidal & cytotoxic peptides made by neutrophils. Beta Defensin-1 is an antimicrobial peptide having the resistance of epithelial surfaces to microbial colonization. Beta Defensin-1 has close proximity to Defensin Alpha-1 and has been implicated in the pathogenesis of cystic fibrosis.
Skin of patients having atopic dermatitis patients and mycosis fungoides (non-lesional and lesional) show lower human Beta Defensin-1 mRNA expression and higher human Beta Defensin-2 and human Beta Defensin-3 mRNA expression.
Beta Defensin is highly expressed by epithelial cells.
Beta-defensin 1 may play a role in the pathogenesis of severe sepsis.