Cytokine induction in HTLV‐I associated myelopathy and adult T‐cell leukemia: Alternate molecular mechanisms underlying retroviral pathogenesis

Abstract

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.

In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

“…Cytokines such as IL-10 and TGF-β have been related to the development of HAM/TSP (28). The levels of TGF-β receptor II (TGF-βRII) as well as Smad7 (a TGF-β-inducible gene) could be reduced in CD4 + T cells of HAM/TSP patients compared with healthy donors (16).…”

Human T Cell Lymphotropic Virus Type I Tax Activates IL-15Rα Gene Expression Through an NF-κB Site

“…In ex vivo cultures, T cells of HAM/TSP patients undergo spontaneous proliferation in the absence of exogenous cytokine or growth factors (41,42). The spontaneous proliferation of these T cells has been attributed to the Tax-induced overexpression of IL-2 and IL-2R␣ which results in the establishment of autocrine and paracrine loops (35,43,44). However, recent data suggest that IL-15 can also contribute to the spontaneous proliferation of these T cells (31).…”

“…Tax is a viral protein that activates the expression of an array of host cell genes including those of IL-2, IL-2R␣, and IL-15 (30,35,43,44). To examine the role of Tax on IL-15R␣ expression, we transfected a Tax expression plasmid (Tax/pMT2T) into Jurkat cells.…”

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

“…It has also been shown that HTLV-I infected dendritic cells from HAM/TSP patients exhibit an enhanced capacity to stimulate antigen-specific CD4ϩ and CD8ϩ T-cell activation, which leads to autoimmunity (8). In sharp contrast ATL pathogenesis is characterized by monoclonal expansion of infected cells, very low proviral loads, absence of pro-inflammatory cytokines (9), and very low frequency of virus-specific CTL (10,11). HTLV-I-infected monocytes produce dysfunctional dendritic cells because of improper differentiation, which do not stimulate autologous T-cells (12).…”