Glatiramer acetate modulates TNF-α and IL-10 secretion in microglia and promotes their phagocytic activity.
Glatiramer acetate (GA) is an approved immunomodulating agent for the treatment of relapsing-remitting multiple sclerosis. Its mode of action is attributed to a T helper cell-type 1 (Th1) to Th2 cytokine shift in T cells. Th2-type GA-reactive T cells migrate into the brain and act suppressive at the sites of inflammation. However, there is increasing evidence that the effect of GA is not confined to T cells. It inhibits broadly the activation of monocytes and induces peritoneal macrophages and monocytes to differentiate into a type 2 antigen-presenting cell (APC) secreting anti-inflammatory cytokines. Thus, we examined whether GA has also direct effects on microglia cells which are involved in modifying/directing the local microenvironment in the central nervous system. Primary rat microglia were purified and cultured under standard conditions. Griess reaction was used to measure one of the stable end products of nitric oxide (NO), nitrite. Tumor necrosis factor (TNF)-alpha and interleukin-10 (IL-10) were measured in the cell culture supernatants using ELISA. Phagocytosis was quantified with a FACS-based assay. Our experiments show that GA directly modulates microglia cells. It promotes the phagocytic activity and increases the secretion of IL-10 while it decreases that of TNFα. In contrast, there was no effect on NO production. GA induces a type 2 APC differentiation of microglia suggesting a general effect on myeloid monocytic cells. Using microglia we report for the first time that GA promotes phagocytosis which could play an important role in removal of debris.
Department of Neurology, Hannover Medical School, Carl-Neuberg-Str-1 30625, Hannover, Germany.
Refik
R
Pul
Darius
D
Moharregh-Khiabani
Jelena
J
Škuljec
Thomas
T
Skripuletz
Niklas
N
Garde
Elke Verena
EV
Voss
Martin
M
Stangel
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D000068717:Glatiramer Acetate; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007166:Immunosuppressive Agents; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000068717:Glatiramer Acetate