ICAM-1-induced expression of proinflammatory cytokines in astrocytes: Involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways

Abstract

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 he 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-1 alpha, IL-1 beta, IL-6, and TNF-alpha. Examination of cytokine protein production revealed that ICAM-1 ligation results in IL-6 secretion by astrocytes, whereas IL-1 beta and IL-1 alpha 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 invoked in ICAM-1-induced IL-6 expression, whereas only ERK1/2 is important for IL-1 alpha and IL-1 beta 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.