The heterodimer STAT1 STAT2 is then translocated into the nucleus where it can bind specific promoters playing a key order inhibitor role in IFN signaling and production. Besides STAT1 and ADAR, Inhibitors,Modulators,Libraries IFN regulated chemokines have become another important topic of research in recent years. Two of these chemokines have been shown to be SLE biomarkers, and they are called C C motif chemo kine ligand 2 and C X C motif chemokine 10. CCL2, formerly referred to as monocyte chemotactic protein 1, is a potent recruiter of monocytes, T cells, basophils, and dendritic cells to the site of infection or tissue damage, but it has no effect on neu trophils or eosinophils unless the N terminus of CCL2 is cleaved. Some cell types such as monocytes, macro phages, and dendritic cells can primarily secrete CCL2, which signals via the cell surface receptors CCR2 and CCR4 and is upregulated by IFN and IFNB.
The role of CCL2 is beneficial in clearing pathogens, but it has also been involved in some pathological processes. In a glomerulonephritis Inhibitors,Modulators,Libraries mouse model, CCL2 plays a role in crescent formation and interstitial fibrosis supported by the observation that anti CCL2 antibodies can reduce crescent formation, renal impairment, and scarring, as well as T cell and macrophage infiltration. CCL2 has been observed in the recruitment of T cells and monocytes macrophages in lupus nephritis and blockade of CCL2 ameliorates Inhibitors,Modulators,Libraries lupus nephritis in MRL lpr mice. In a serologic proteome study by antibody microarray in SLE, CCL2 was identified as one of the twelve upregulated proteins.
fur thermore CCL2 was one of three chemokines that would precede Inhibitors,Modulators,Libraries lupus flare, indicating that they are good predictors of increased SLE activity. CXCL10, also known as IFN gamma induced protein 10, is a chemokine of the C X C motif family. Similar to CCL2, CXCL10 is a potent attractor of mono cytes, macrophages, T cells, natural killer cells, and dendritic cells to sites of tissue damage Inhibitors,Modulators,Libraries and infection. CXCL10 is an IFN response cytokine that binds its CCL3 receptor and acts via Jak STAT pathway activa tion. Even though CXCL10 is a potent immune responder for bacterial and viral infections and a critical biomarker for organ transplant rejection, its role in the pathogenesis of autoimmune diseases is not clear. Furthermore, the combination of CXCL10 and CCL2 protein levels could be useful as prediction factor for up coming flares.
The reason behind upregulation and control of IFN in SLE is not known, but some studies have recently focused on the possible role played by selected micro RNAs. MiRNAs are small non encoding 20 to 23 nucleotide long RNAs, that regulate their target mRNA by binding to the 3 UTR, causing translational repression Seliciclib and or degradation of targets. miR 146a is one of the most significant miRNAs in regulating innate immune response and tolerance and it was first shown to be involved in toll like receptor regulation through the nuclear factor ��B pathway.