Effects of Oncostatin M on Human Cerebral Endothelial Cells and Expression in Inflammatory Brain Lesions

Abstract

Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.

Mechanism of plasminogen activator inhibitor‐1 regulation by oncostatin M and interleukin‐1 in human astrocytes

“…We have previously reported that OSM is produced by microglia in culture (Kordula et al 1998). Recently, OSM has been detected in microglia, reactive astrocytes, and leukocytes infiltrating the brains of multiple sclerosis patients; whereas OSM was not expressed in normal brains or brains of patients with non-inflammatory neurological diseases (Ruprecht et al 2001). There are also numerous reports indicating that IL-1 is found in the CNS and it is involved in many physiological and pathological processes.…”

Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis

“…This hypothesis is suggested by the observation of significantly reduced T-cell infiltration and diffuse microglia activation within the noninflamed spinal cord parenchyma and a significant reduction of Ig leakage in spinal cord tissue of 74 Although expression of CNTFR␣ mRNA was not detected, 74 requirement for the nonsignaling chain can be bypassed by the formation of complexes between CNTF and soluble CNTFR␣. 14 The CNTF doses used in our EAE experiments are in same range as other studies in which CNTF or LIF were administered systemically.…”

Blood cells and endothelial barrier function

“…106 OSM may also promote BBB dysfunction by stimulating brain cells to produce cytokines and prostaglandins, 107,108 and to increase the expression of cell adhesion molecules on endothelial cells. 109 While monocytes are the dominant source of OCM produced by blood cells, activated microglia and astrocytes are additional sources of OCM in the brain. Monocytes are also a rich source of VEGF.…”