minocycline and Paraparesis--Tropical-Spastic

Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).. The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines.. The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.

Topics: Adult; Anti-Bacterial Agents; Cell Line; Chemokine CCL1; Down-Regulation; Flow Cytometry; Gene Products, tax; Humans; Minocycline; Paraparesis, Tropical Spastic; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Receptors, CCR8; Transcriptional Activation; Up-Regulation

The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases.. Phenotypic analysis of CD14⁺ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16⁺ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-α and IL-1β in cultured CD14⁺ cells of HAM/TSP patients. CD14⁺ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4⁺ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-α expression in CD14⁺ cells and IL-1β release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-γ expression in CD8⁺ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-γ expression in CD8⁺ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14⁺ cells.. These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8⁺ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.

Topics: Antigens, Viral; Cells, Cultured; Human T-lymphotropic virus 1; Humans; Immunosuppressive Agents; Interleukin-1beta; Lipopolysaccharide Receptors; Minocycline; Paraparesis, Tropical Spastic; Phagocytes; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha