Molecular mechanism of aberrant activation of cytokine expressions and immunodeficiency by HTLV-1 infection
| Project/Area Number |
17590983
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Niigata University |
|---|
Principal Investigator |
MASAHIRO Fujii Niigata University, Institute of Medicine and Dentistry, Professor, 医歯学系, 教授 (30183099)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | HTLV-1 / Virus / leukemia / ATL / NF-kB / NFAT / Tax / 微生物 / サイトカイン / Tax / NFAT / IL-2 / AP-1 |
|---|
| Research Abstract |
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia (ATL), and the distinct pathogenecity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. We found two crucial differences between Tax1 and Tax2. 1, Tax1 but not Tax2 interacts with NF-kB2/p100, and activates it by inducing the cleavage of p100 into the active transcription factor, p52. The RNA interference method demonstrated that NF-kB2/p100 is required for the transformation induced by Tax1 but not Tax2, as determined by their ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2) dependent growth into independent growth. While Tax2 showed a reduced transforming activity relative to Tax1, a Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 showed an equivalent transforming activity to Tax1 in CTLL-2 expressing an inducer of p52 processing (an active form of NF-κB inducing kinase). These results reveal the activation of NF-κB2/p100 to play a crucial role in the Tax1-mediated transformation of T-cells, and NF-κB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2. 2, Tax2 stimulated gene expression of interleukin (IL)-2 through the nuclear factor of activated T cells (NFAT). However, the activity of HTLV-1 Tax1 was minimal in this system. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells.
Our results suggest that the distinct transformation mechanism of Tax1 relative to Tax2 play crucial role in HTLV-1 specific leukemogenesis.
|
Report
(3 results)
Research Products
(24 results)
