ABSTRACT
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mediated by blood-derived immune cells invading the CNS. This invasion could be determined by chemokines, and their role within the MS-affected brain is still poorly defined. We investigated the expression by RT-PCR and protein release by ELISA of the interferon-gamma (IFN-gamma)-inducible chemokines in human brain microvascular endothelial cells (HBMECs) and astrocytes. The monokine induced by IFN-gamma (Mig) behaves as a homing chemokine constitutively expressed in HBMECs and astrocytes, whereas the IFN-gamma-inducible 10-kDa protein (IP-10) and IFN-inducible T cell alpha-chemoattractant (I-TAC) are induced only after inflammatory stimuli. The biologic activity of IFN-gamma-inducible chemokines from an endothelial source was analyzed, and the transendothelial migration of activated lymphocytes was partly antagonized by specific antibodies, especially anti-Mig antibody. Our data highlight the capability of cells of the CNS to activate the chemoattractant machinery in a proinflammatory environment and in MS.
Subject(s)
Astrocytes/drug effects , Brain/metabolism , Chemokines, CXC/genetics , Chemokines, CXC/metabolism , Endothelium, Vascular/metabolism , Intercellular Signaling Peptides and Proteins , Interferon-gamma/pharmacology , Interleukin-10/genetics , Multiple Sclerosis/etiology , Antibodies/pharmacology , Astrocytes/immunology , Astrocytes/metabolism , Brain/blood supply , Brain/cytology , Cells, Cultured , Chemokine CXCL10 , Chemokine CXCL11 , Chemokine CXCL9 , Chemokines, CXC/biosynthesis , Chemotaxis, Leukocyte/immunology , Culture Media, Conditioned , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Gene Expression Profiling , Humans , Interleukin-10/biosynthesis , Interleukin-10/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Microcirculation , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , RNA, Messenger/metabolismABSTRACT
CSF and serum levels of soluble Fas were studied in MS patients, in patients with various neurological diseases and in healthy controls. We did not detect differences in serum sFas levels between MS patients and controls. In CSF, despite sFas levels being similar in all patients studied, a statistically significant correlation between sFas CSF/sFas serum ratio and BBB damage (expressed as albumin CSF/albumin serum ratio) was detected in non-MS neurological disease, but not in MS patients. The normalized ratio (sFas CSF/sFas serum)/(Alb CSF/Alb serum) was significantly increased in MS patients compared to patients with non-inflammatory neurological disease suggesting an intrathecal synthesis of soluble Fas in MS. The percentage of apoptotic mononuclear cells was higher in CSF as compared to peripheral blood; moreover a lower proportion of apoptotic cells was found in CSF of MS patients. The findings lend support to the involvement of sFas in MS pathogenesis and suggest that a lower apoptosis in CSF may be a feature of the disease.