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Lymphokine induction of rat microglia multinucleated giant cell formation
T T Lee1, F C Martin, J E Merrill
1Department of Neurology, Reed Neurological Research Center, UCLA School of Medicine 90024-1769.
Abstract:
Multinucleated giant cell formation (MNGC) occurs in central nervous system AIDS. The mechanism of fusion of microglia in these cases is unknown. We investigated the ability of lymphokines to induce fusion and found that interleukin-3 (IL-3), interleukin-4 (IL-4), gamma interferon (gamma-IFN), and granulocyte-macrophage colony stimulating factor (GM-CSF) induced MNGC formation in cultures of rat microglia in vitro. The diacylglycerol analogue phorbol myristate acetate (PMA) also induced MNGC. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) failed to induce fusion. Preincubation of the IL-3 treated cultures with anti-IL-3, anti-leukocyte function associated antigen-1 (LFA-1) alpha-chain (CD11a), and anti-intercellular adhesion molecule-1 (ICAM-1) inhibited cell fusion. Antibody to polymorphic Class II major histocompatibility complex (MHC) determinants also inhibited MNGCs. Cell surface LFA-1 was predominantly observed on MNGC, suggesting that LFA-1 expression is involved in microglia fusion. We thus propose that MNGC formation of microglia result from the effects of T cell-derived cytokines probably through the induction of cell surface adhesion molecules.
Insights
Cytokines like interleukin-3 (IL-3) and gamma interferon (gamma-IFN) can induce multinucleated giant cell (MNGC) formation in microglia. This process may involve cell adhesion molecules such as LFA-1 and ICAM-1.
Area of Science:
- Neuroimmunology
- Cell Biology
- AIDS Pathogenesis
Background:
- Multinucleated giant cell (MNGC) formation is observed in the central nervous system (CNS) in cases of acquired immunodeficiency syndrome (AIDS).
- The precise mechanisms driving the fusion of microglia, the resident immune cells of the CNS, in this context remain poorly understood.
Purpose of the Study:
- To investigate the role of lymphokines in inducing microglia fusion and MNGC formation.
- To identify specific cytokines and cell surface molecules involved in this fusion process.
Main Methods:
- Cultures of rat microglia were treated with various lymphokines, including interleukin-3 (IL-3), IL-4, gamma interferon (gamma-IFN), and granulocyte-macrophage colony stimulating factor (GM-CSF).
- The effect of phorbol myristate acetate (PMA) on MNGC formation was also assessed.
- Inhibition studies were performed using antibodies against IL-3, leukocyte function associated antigen-1 (LFA-1) alpha-chain (CD11a), and intercellular adhesion molecule-1 (ICAM-1).
- Antibodies targeting polymorphic Class II major histocompatibility complex (MHC) determinants were also used.
Main Results:
- IL-3, IL-4, gamma-IFN, and GM-CSF were found to induce MNGC formation in rat microglia cultures in vitro.
- PMA also stimulated MNGC formation.
- Interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF alpha) did not induce fusion.
- Preincubation with anti-IL-3, anti-LFA-1, and anti-ICAM-1 antibodies significantly inhibited IL-3-induced cell fusion.
- Antibodies against MHC Class II determinants also inhibited MNGC formation.
- Cell surface LFA-1 expression was notably higher on MNGCs, suggesting its involvement in microglia fusion.
Conclusions:
- T cell-derived cytokines, likely through the induction of cell surface adhesion molecules like LFA-1 and ICAM-1, are proposed to mediate MNGC formation in microglia.
- This finding provides insight into the cellular mechanisms underlying neuropathology in CNS AIDS.