The HTLV-I p30 Interferes with TLR4 Signaling and Modulates the Release of Pro- and Anti-inflammatory Cytokines from Human Macrophages

Abhik Datta, Uma Sinha-Datta, Navneet Kaur Dhillon, Shilpa Buch, Christophe Nicot
2006 Journal of Biological Chemistry  
Whereas adaptive immunity has been extensively studied, very little is known about the innate immunity of the host to HTLV-I infection. HTLV-I-infected ATL patients have pronounced immunodeficiency associated with frequent opportunistic infections, and in these patients, concurrent infections with bacteria and/or parasites are known to increase risks of progression to ATL. The Toll-like receptor-4 (TLR4) activation in response to bacterial infection is essential for dendritic cell maturation
more » ... cell maturation and links the innate and adaptive immune responses. Recent reports indicate that TLR4 is targeted by viruses such as RSV, HCV, and MMTV. Here we report that HTLV-I has also evolved a protein that interferes with TLR4 signaling; p30 interacts with and inhibits the DNA binding and transcription activity of PU.1 resulting in the down-regulation of the TLR4 expression from the cell surface. Expression of p30 hampers the release of pro-inflammatory cytokines MCP-1, TNF-␣, and IL-8 and stimulates release of anti-inflammatory IL-10 following stimulation of TLR4 in human macrophage. Finally, we found that p30 increases phosphorylation and inactivation of GSK3-␤ a key step for IL-10 production. Our study suggests a novel function of p30, which may instigate immune tolerance by reducing activation of adaptive immunity in ATL patients. Human T cell leukemia virus type I (HTLV-I), 2 is the etiologic agent of lymphoproliferative diseases known as adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) (1-3). Adaptive immunity in patients with HTLV-I associated ATL or HAM/ TSP has been extensively studied. HTLV-I-associated neurological disorders HAM/TSP are characterized by polyclonal
doi:10.1074/jbc.m600684200 pmid:16785240 fatcat:x2wapzr4r5agbmsrmie7ecoxoy