Abstract

The production of IL-10, which counteracts the effect of pro-inflammatory cytokines such as TNF-alpha, is induced by HIV-1 Tat in monocytes/macrophages by a process regulated by CREB-1 transcription factors [1]. IL-10 has been reported to suppress HIV-1 replication in macrophages by inhibiting HIV-1 transcription [2] at a, but it has also been reported to contribute to cell-mediated immunity in the setting of HIV infection [3]. We compared Tat-induced expression of IL-10 by THP-1 monocytes at 3% O2 (20 mmHg), the tension that monocytes see in certain tissues, and atmospheric 21% O2 (150 mmHg), the conventional in vitro culture condition. THP-1 cells were treated with recombinant HIV-Tat protein in combination with or without lipopolysaccharide (LPS) and IL-10 expression was analyzed by RT-PCR and ELISA. Treatment of THP-1 cells with HIV-Tat and LPS resulted in a dose- and time-dependent increase in IL-10 expression in the cells cultured at 21% O2. In contrast under 3% O2 the expression of IL-10 was reduced by 3-fold. Treatment with tautomycin, a protein phosphatase-1 (PP1) inhibitor, prevented IL-10 expression in LPS-stimulated THP-1 cells cultured at 21% O2. Thus, PP1 is likely to participate in Tat-mediated IL-10 production. PP1 has shown to affect CREB activity [4]; therefore we propose that PP1 might be involved in the CREB-mediated IL-10 gene expression. The inability of Tat to induce IL-10 production under 3% O2 might reflect the inadequate response of HIV-1 infected macrophages in vivo that might permit viral replication in infected macrophages. Further investigation of the role of PP1 in IL-10 expression could lead to new therapeutic opportunities for HIV-1 infection.

References

References
1
Gee, K., Angel, J. B., Ma, W., Mishra, S., Gajanayaka, N., Parato, K. & Kumar, A. (
2006
) Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells,
J Biol Chem.
281
,
31647
–58.
2
Wang, Y. & Rice, A. P. (
2006
) Interleukin-10 inhibits HIV-1 LTR-directed gene expression in human macrophages through the induction of cyclin T1 proteolysis,
Virology
.
352
,
485
–92.
3
Kedzierska, K. & Crowe, S. M. (
2001
) Cytokines and HIV-1: interactions and clinical implications,
Antivir Chem Chemother.
12
,
133
–50.
4
Comerford, K. M., Leonard, M. O., Cummins, E. P., Fitzgerald, K. T., Beullens, M., Bollen, M. & Taylor, C. T. (
2006
) Regulation of protein phosphatase 1gamma activity in hypoxia through increased interaction with NIPP1: implications for cellular metabolism,
J Cell Physiol.
209
,
211
–8.

Author notes

Disclosure: No relevant conflicts of interest to declare.