The upregulation of CC chemokine receptor 7 and the increased migration of maturing dendritic cells to macrophage inflammatory protein 3beta and secondary lymphoid chemokine is mediated by the p38 stress-activated protein kinase pathway.
Using the p38 stress-activated protein kinase (p38SAPK) inhibitor, SB203580, increased responsiveness of monocyte-derived dendritic cells (MoDCs) to secondary lymphoid chemokine (SLC) and macrophage inflammatory protein 3beta (MIP3beta), following lipopolysaccharide-induced MoDC maturation, was shown to be mediated by the p38SAPK pathway. This was due to the complete abrogation of upregulation of CC chemokine receptor 7, the receptor for MIP3beta/SLC. Once mature, MoDCs utilized both the p38SAPK and phosphoinositide-3 kinase pathways to migrate in response to SLC or MIP3beta. These findings have implications for the mechanism of action of p38SAPK inhibitors, currently in use in clinical trials for patients with autoimmune diseases.
Ardeshna
Kirit M
KM
Department of Haematology, Royal Free and UCL Medical School, Guy's, King's, St Thomas' School of Medicine, Rayne Institute, London, UK. kirit.ardeshna@uclh.org
Pizzey
Arnold R
AR
Walker
Simon J
SJ
Devereux
Stephen
S
Khwaja
Asim
A
D020533:Angiogenesis Inhibitors / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D016922:Cellular Senescence / Q000187:drug effects; D054418:Chemokine CCL20; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003713:Dendritic Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D020533:Angiogenesis Inhibitors; D002070:Butadienes; C108355:CCL20 protein, human; C515478:CCL21 protein, human; C106311:CCR6 protein, human; C515370:CCR7 protein, human; D054418:Chemokine CCL20; D054421:Chemokine CCL21; D019742:Chemokines, CC; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D009025:Morpholines; D009570:Nitriles; D011725:Pyridines; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580