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Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells.
Br J Haematol 1995; 91(1):8-14BJ

Abstract

Recently it has been shown that IFN-alpha inhibits expression of GM-CSF in adherent cells of human long-term bone marrow cultures (LTBMC) stimulated with interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) or endotoxin. The murine bone marrow stromal cell line +/+(-1).LDA11 was used to further define regulatory mechanisms of IFN-alpha inhibition on GM-CSF expression. This cell line originated from a murine Dexter type culture and exhibits a preadipocytic phenotype. As in human LTBMC, we could demonstrate a inhibitory effect of IFN-alpha co-incubation on GM-CSF activity in serum-free supernatants of +/+(-1).LDA11 stromal cell cultures stimulated with IL-1 or TNF-alpha or the combination of IL-1 plus TNF-alpha. IFN-alpha inhibitory effect on GM-CSF expression was shown to be dose dependent with minimal response at 10 U/ml and maximal inhibition at a dose of 500 U/ml. Northern blot analysis confirmed these data at the mRNA level. Reprobing of Northern blots for interleukin-6 (IL-6) mRNA showed increased expression after IFN-alpha incubation, demonstrating specific and differential regulatory effects of IFN-alpha on cytokine production in bone marrow stromal cells. Inhibition of GM-CSF mRNA by IFN-alpha was time dependent, starting at about 90-120 min post-treatment. Cycloheximide (CHX) incubation abolished the inhibitory effect of IFN-alpha on GM-CSF expression, suggesting the requirement of a labile protein. Reporter gene studies were used in order to evaluate the effect of IFN-alpha incubation on GM-CSF mRNA transcription in stromal cells. For this purpose, GM-CSF promoter fragments were subcloned into a luciferase expression vector. Neither constitutive nor TNF-alpha stimulated GM-CSF transcription was inhibited by IFN-alpha coincubation. On the other hand, actinomycin-D chase experiments revealed a reduced GM-CSF mRNA stability after IFN-alpha incubation. The induction of a RNAase, possibly a 2-5A-dependent RNAase, by IFN-alpha may be a possible cause for the increased GM-CSF mRNA decay. These results show a regulatory role for IFN-alpha in the bone marrow microenvironment possibly involved in the myelosuppressive effect of IFN-alpha therapy or viral infections.

Authors+Show Affiliations

III. Department of Medicine, Johannes Gutenber-Universität, Mainz, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7577656

Citation

Göllner, G, et al. "Interferon-alpha (IFN-alpha) Inhibits Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) Expression at the Post-transcriptional Level in Murine Bone Marrow Stromal Cells." British Journal of Haematology, vol. 91, no. 1, 1995, pp. 8-14.
Göllner G, Aman MJ, Steffens HP, et al. Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells. Br J Haematol. 1995;91(1):8-14.
Göllner, G., Aman, M. J., Steffens, H. P., Huber, C., Peschel, C., & Derigs, H. G. (1995). Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells. British Journal of Haematology, 91(1), pp. 8-14.
Göllner G, et al. Interferon-alpha (IFN-alpha) Inhibits Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) Expression at the Post-transcriptional Level in Murine Bone Marrow Stromal Cells. Br J Haematol. 1995;91(1):8-14. PubMed PMID: 7577656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells. AU - Göllner,G, AU - Aman,M J, AU - Steffens,H P, AU - Huber,C, AU - Peschel,C, AU - Derigs,H G, PY - 1995/9/1/pubmed PY - 1995/9/1/medline PY - 1995/9/1/entrez SP - 8 EP - 14 JF - British journal of haematology JO - Br. J. Haematol. VL - 91 IS - 1 N2 - Recently it has been shown that IFN-alpha inhibits expression of GM-CSF in adherent cells of human long-term bone marrow cultures (LTBMC) stimulated with interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) or endotoxin. The murine bone marrow stromal cell line +/+(-1).LDA11 was used to further define regulatory mechanisms of IFN-alpha inhibition on GM-CSF expression. This cell line originated from a murine Dexter type culture and exhibits a preadipocytic phenotype. As in human LTBMC, we could demonstrate a inhibitory effect of IFN-alpha co-incubation on GM-CSF activity in serum-free supernatants of +/+(-1).LDA11 stromal cell cultures stimulated with IL-1 or TNF-alpha or the combination of IL-1 plus TNF-alpha. IFN-alpha inhibitory effect on GM-CSF expression was shown to be dose dependent with minimal response at 10 U/ml and maximal inhibition at a dose of 500 U/ml. Northern blot analysis confirmed these data at the mRNA level. Reprobing of Northern blots for interleukin-6 (IL-6) mRNA showed increased expression after IFN-alpha incubation, demonstrating specific and differential regulatory effects of IFN-alpha on cytokine production in bone marrow stromal cells. Inhibition of GM-CSF mRNA by IFN-alpha was time dependent, starting at about 90-120 min post-treatment. Cycloheximide (CHX) incubation abolished the inhibitory effect of IFN-alpha on GM-CSF expression, suggesting the requirement of a labile protein. Reporter gene studies were used in order to evaluate the effect of IFN-alpha incubation on GM-CSF mRNA transcription in stromal cells. For this purpose, GM-CSF promoter fragments were subcloned into a luciferase expression vector. Neither constitutive nor TNF-alpha stimulated GM-CSF transcription was inhibited by IFN-alpha coincubation. On the other hand, actinomycin-D chase experiments revealed a reduced GM-CSF mRNA stability after IFN-alpha incubation. The induction of a RNAase, possibly a 2-5A-dependent RNAase, by IFN-alpha may be a possible cause for the increased GM-CSF mRNA decay. These results show a regulatory role for IFN-alpha in the bone marrow microenvironment possibly involved in the myelosuppressive effect of IFN-alpha therapy or viral infections. SN - 0007-1048 UR - https://www.unboundmedicine.com/medline/citation/7577656/Interferon_alpha__IFN_alpha__inhibits_granulocyte_macrophage_colony_stimulating_factor__GM_CSF__expression_at_the_post_transcriptional_level_in_murine_bone_marrow_stromal_cells_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=1995&volume=91&issue=1&spage=8 DB - PRIME DP - Unbound Medicine ER -