Transforming growth factor beta: is it a downregulator of stem cell inhibition by macrophage inflammatory protein 1 alpha?

doi:10.1084/jem.178.3.925

This Article

	Full Text (PDF, 1023K)
	Alert me when this article is cited

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Maltman, J.
	Articles by Graham, G. J.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Maltman, J.
	Articles by Graham, G. J.


Social Bookmarking

	What's this?

ARTICLES

Transforming growth factor beta: is it a downregulator of stem cell inhibition by macrophage inflammatory protein 1 alpha?

J Maltman, IB Pragnell and GJ Graham
Beatson Institute for Cancer Research, Glasgow, UK.

Transforming growth factor beta 1 (TGF-beta 1) and macrophage inflammatory protein 1 alpha (MIP-1 alpha) have recently been identified as potent inhibitors of hemopoietic stem cell proliferation. From previous studies, these molecules appear to have similar functions in the control of stem cell proliferation. This study was designed to investigate the relationship, if any, between these two negative regulators in an attempt to elucidate possible distinctive roles for each within the hemopoietic system. We report here that both MIP-1 alpha and TGF-beta are capable of inhibiting the same stem cell population (colony-forming unit [CFU]-A/CFU-S) with similar potencies. We further show that TGF-beta potently inhibits MIP-1 alpha gene expression in bone marrow-derived macrophages, the presumed source of MIP-1 alpha in the bone marrow. This inhibition is not specific to MIP- 1 alpha in that expression of MIP-1 beta, a related molecule that does not exhibit potent stem cell inhibitory properties, is inhibited in a similar manner. The inhibition of MIP-1 alpha gene expression is also seen as a reduction in MIP-1 alpha protein production, which markedly decreases 24 h after treating RAW 264.7 cells, a murine macrophage cell line, with TGF-beta. These in vitro results suggest that in the presence of active TGF-beta in vivo, and in the absence of upregulators of MIP-1 alpha transcription, very little MIP-1 alpha will be produced. To address how MIP-1 alpha's target cells, the stem cells, would respond to TGF-beta, and the consequently low levels of MIP-1 alpha produced, we analyzed the effect of TGF-beta on MIP-1 alpha receptor levels on FDCP-MIX cells, a murine stem cell line. We show that TGF- beta (100 pM) reversibly downregulates MIP-1 alpha receptor levels on these cells to a maximum of 50-70% after 24 h. This level of downregulation does not change upon increasing the concentration of TGF- beta or the length of exposure of the cells to TGF-beta. Scatchard analysis shows that TGF-beta downregulates MIP-1 alpha receptor numbers with no change in affinity of the remaining receptors. These results suggest that TGF-beta may be capable of interfering with MIP-1 alpha's role as a stem cell inhibitor. Indeed, they suggest that in the presence of active TGF-beta in vivo, MIP-1 alpha is at best a weak contributor to the overall physiological inhibition of stem cells.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Hsieh, C.-H., Frink, M., Hsieh, Y.-C., Kan, W.-H., Hsu, J.-T., Schwacha, M. G., Choudhry, M. A., Chaudry, I. H. (2008). The Role of MIP-1{alpha} in the Development of Systemic Inflammatory Response and Organ Injury following Trauma Hemorrhage. J. Immunol. 181: 2806-2812 [Abstract] [Full Text]
Wright, N., de Lera, T. L., Garcia-Moruja, C., Lillo, R., Garcia-Sanchez, F., Caruz, A., Teixido, J. (2003). Transforming growth factor-{beta}1 down-regulates expression of chemokine stromal cell-derived factor-1: functional consequences in cell migration and adhesion. Blood 102: 1978-1984 [Abstract] [Full Text]
Paukovits, J. B., Rutter, R., Ganglberger, E., Karlic, H. I., Marian, B., Paukovits, W. R. (1999). The Hemoregulatory Peptide pEEDCK May Inhibit Stem Cell Proliferation via Hydropathic Binding to Antisense Sequence Motifs in Interleukin-11 and Other Growth Factors. Mol. Pharmacol. 56: 665-674 [Abstract] [Full Text]
Durig, J., de Wynter, E. A., Kasper, C., Cross, M. A., Chang, J., Testa, N. G., Heyworth, C. M. (1998). Expression of Macrophage Inflammatory Protein-1alpha Receptors in Human CD34+ Hematopoietic Cells and Their Modulation by Tumor Necrosis Factor-alpha and Interferon-gamma. Blood 92: 3073-3081 [Abstract] [Full Text]