IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions.
We investigated T cell receptor induced IL-18 secretion, the cellular and molecular mechanisms associated with the induction of IL-18 and the role of IL-18 in IFN-gamma production in the different stages of multiple sclerosis (MS). We found that anti-CD3/CD28 induced IL-18 production by peripheral blood mononuclear cells was increased in both relapsing-remitting and secondary progressive MS. In controls and relapsing-remitting MS neutralizing anti-IL-12 and anti-IL-18 alone equally suppressed IFN-gamma production whereas in progressive MS, maximum suppression of IFN-gamma was only observed when neutralizing anti-IL-12 and anti-IL-18 were given together, suggesting that in progressive MS, IL-12 and IL-18 function in a non-linked manner to induce IFN-gamma. Elevated IL-18 production in MS was dependent on the interaction of antigen presenting cells with activated CD4(+) T cells via CD40-CD40 ligand and the levels of IL-18 correlated with disease duration in secondary progressive MS. These results demonstrated that IL-18 has an important role in augmenting Th-1 type immune responses in MS and may be involved in immune changes that occur when patients enter the progressive stage.
Karni
Arnon
A
Center for Neurologic Diseases, Brigham and Women's and Massachusetts General Hospitals, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Koldzic
Djordje N
DN
Bharanidharan
Padmanabhan
P
Khoury
Samia J
SJ
Weiner
Howard L
HL
D000328:Adult; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053724:Receptors, Interleukin-18
D018106:CD28 Antigens; D017252:CD3 Complex; D019013:CD40 Antigens; C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma