Mechanisms of disease: regulation of RANTES (CCL5) in renal disease.
Chemokines (chemoattractant cytokines) are fundamental regulators of immune cell movement from the bloodstream into tissues. Regulating expression of chemokines might, therefore, alleviate inflammation in autoimmune diseases and transplant rejection, or augment immune responses in cancer and immunodeficiency. RANTES (regulated upon activation, normal T cell expressed and secreted [also known as CCL5]) is a model chemokine of relevance to a myriad of diseases. Regulation of RANTES expression is complex. In fibroblasts and monocytes, rel proteins alone suffice to induce transcription of RANTES. By contrast, expression of RANTES in T lymphocytes 3-5 days after activation requires the development of a molecular complex (enhancesome) including KLF13 (Krueppel-like factor 13), rel proteins p50 and p65, and scaffolding proteins. This complex recruits enzymes involved in acetylation, methylation and phosphorylation of chromatin, and ultimately in the expression of RANTES. In addition, KLF13-the lynchpin for recruitment of this molecular complex-is itself translationally regulated. Such complex regulation of biological systems has major implications for the rational design of drugs aimed at increasing or decreasing inflammatory responses in patients.
Krensky
Alan M
AM
Division of Immunology and Transplantation Biology in the Department of Pediatrics at Stanford University School of Medicine, Stanford, CA, USA. krensky@stanford.edu
Ahn
Yong-Tae
YT
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D005786:Gene Expression Regulation; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D018946:Chemokine CCL5; C486423:KLF13 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins