ICAM-1-induced expression of proinflammatory cytokines in astrocytes: involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways.
ICAM-1 is a transmembrane glycoprotein of the Ig superfamily involved in cell adhesion. ICAM-1 is aberrantly expressed by astrocytes in CNS pathologies such as multiple sclerosis, experimental allergic encephalomyelitis, and Alzheimer's disease, suggesting a possible role for ICAM-1 in these disorders. ICAM-1 has been shown to be important for leukocyte diapedesis through brain microvessels and subsequent binding to astrocytes. However, other functional roles for ICAM-1 expression on astrocytes have not been well elucidated. Therefore, we investigated the intracellular signals generated upon ICAM-1 engagement on astrocytes. ICAM-1 ligation by a mAb to rat ICAM-1 induced mRNA expression of proinflammatory cytokines such as IL-1alpha, IL-1beta, IL-6, and TNF-alpha. Examination of cytokine protein production revealed that ICAM-1 ligation results in IL-6 secretion by astrocytes, whereas IL-1beta and IL-1alpha protein is expressed intracellularly in astrocytes. The involvement of mitogen-activated protein kinases (MAPKs) in ICAM-1-mediated cytokine expression in astrocytes was tested, as the MAPK extracellular signal-regulated kinase (ERK) was previously shown to be activated upon ICAM-1 engagement. Our results indicate that ERK1/ERK2, as well as p38 MAPK, are activated upon ligation of ICAM-1. Studies using pharmacological inhibitors demonstrate that both p38 MAPK and ERK1/2 are involved in ICAM-1-induced IL-6 expression, whereas only ERK1/2 is important for IL-1alpha and IL-1beta expression. Our data support the role of ICAM-1 on astrocytes as an inflammatory mediator in the CNS and also uncover a novel signal transduction pathway through p38 MAPK upon ICAM-1 ligation.
Lee
S J
SJ
Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA.
Drabik
K
K
Van Wagoner
N J
NJ
Lee
S
S
Choi
C
C
Dong
Y
Y
Benveniste
E N
EN
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007106:Immune Sera / Q000502:physiology; D007140:Immunoglobulin Fab Fragments / Q000502:physiology; D007166:Immunosuppressive Agents / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008024:Ligands; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004791:Enzyme Inhibitors; D007106:Immune Sera; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008024:Ligands; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases