Mechanisms of Disease: regulation of RANTES (CCL5) in renal disease

Abstract

Epigenetic, or nonheritable, mechanisms that regulate gene expression are potentially reversible. In this short article, authors involved in identification of the chemokine RANTES (CCL5) outline the complex pathways that control its expression and thereby influence movement of immune cells, with a focus on T lymphocytes. Rational design of agents based on this knowledge could have a beneficial impact on various forms of nephritis and nephropathy, transplant rejection and acute renal failure. 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.