The uptake of oxidized low density lipoprotein (ox-LDL) by macrophages usually leads to the formation of lipid-laden macrophages known as "foam cells," and this process plays an important role in the development of atherosclerosis. Ox-LDL activates mitogen-activated protein kinase (MAP) kinases and nuclear factor (NF)-κB, and activations of p38 and NF-κB are important for the formation of foam cells. MAP kinase phosphatase (MKP) 5 is a member of the dual specificity phosphatases (DUSPs) family that can selectively dephosphorylate activated MAPKs to regulate innate and adaptive immune responses. However, the role of MKP5 in the formation of foam cells remains unknown. Here, we found that stimulation of ox-LDL induces the expression of MKP5 in macrophages. MKP5 deficiency blocked the uptake of ox-LDL and the formation of foam cells. Further analysis revealed that deletion of MKP5 reduced the ox-LDL-induced activation of NF-κB. Also, MKP5 deficiency markedly inhibited the production of TNF-α, but enhanced the levels of TGF-β1 in ox-LDL-stimulated macrophages. Moreover, inhibition of NF-κB by p65 RNAi significantly reduced foam cell formation in macrophages from WT mice relative to MKP5-deficient mice. Thus, MKP5 has an essential role in the formation of foam cells through activation of NF-κB, and MKP5 represents a novel target for the therapeutic intervention of atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component.
PLoS ONE 08/2013; 8(8):e70174. DOI:10.1371/journal.pone.0070174 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Significance:
The dual-specificity phosphatases (DUSPs) constitute a heterogeneous group of cysteine-based protein tyrosine phosphatases, whose members exert a pivotal role in cell physiology by dephosphorylation of phosphoserine, phosphothreonine, and phosphotyrosine residues from proteins, as well as other non-proteinaceous substrates.
A picture is emerging in which a selected group of DUSP enzymes display overexpression or hyperactivity that is associated with human disease, especially human cancer, making feasible targeted therapy approaches based on their inhibition. A panoply of molecular and functional studies on DUSPs have been performed in the previous years, and drug-discovery efforts are ongoing to develop specific and efficient DUSP enzyme inhibitors. This review summarizes the current status on inhibitory compounds targeting DUSPs that belong to the MAP kinase phosphatases-, small-sized atypical-, and phosphatases of regenerating liver subfamilies, whose inhibition could be beneficial for the prevention or mitigation of human disease.
Achieving specificity, potency, and bioavailability are the major challenges in the discovery of DUSP inhibitors for the clinics. Clinical validation of compounds or alternative inhibitory strategies of DUSP inhibition has yet to come.
Further work is required to understand the dual role of many DUSPs in human cancer, their function-structure properties, and to identify their physiologic substrates. This will help in the implementation of therapies based on DUSPs inhibition.
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