Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway.

Abstract

BACKGROUND:

The host's response to infection is characterized by altered levels of neurotrophins and an influx of inflammatory cells to sites of injured tissue. Progenitor cells that give rise to the differentiated cellular mediators of inflammation are derived from bone marrow progenitor cells where their development is regulated, in part, by cues from bone marrow stromal cells (BMSC). As such, alteration of BMSC function in response to elevated systemic mediators has the potential to alter their function in biologically relevant ways, including downstream alteration of cytokine production that influences hematopoietic development.

METHODOLOGY/PRINCIPAL FINDINGS:

In the current study we investigated BMSC neurotrophin receptor expression by flow cytometric analysis to determine differences in expression as well as potential to respond to NGF or BDNF. Intracellular signaling subsequent to neurotrophin stimulation of BMSC was analyzed by western blot, microarray analysis, confocal microscopy and real-time PCR. Analysis of BMSC Interleukin-6 (IL-6) expression was completed using ELISA and real-time PCR.

CONCLUSION:

BMSC established from different individuals had distinct expression profiles of the neurotrophin receptors, TrkA, TrkB, TrkC, and p75(NTR). These receptors were functional, demonstrated by an increase in Akt-phosphorylation following BMSC exposure to recombinant NGF or BDNF. Neurotrophin stimulation of BMSC resulted in increased IL-6 gene and protein expression which required activation of ERK and p38 MAPK signaling, but was not mediated by the NFkappaB pathway. BMSC response to neurotrophins, including the up-regulation of IL-6, may alter their support of hematopoiesis and regulate the availability of inflammatory cells for migration to sites of injury or infection. As such, these studies are relevant to the growing appreciation of the interplay between neurotropic mediators and the regulation of hematopoiesis.

• Authors: Fariba Rezaee, Stephanie L Rellick, Giovanni Piedimonte, Stephen M Akers, Heather A O'Leary, Karen Martin, Michael D Craig, Laura F Gibson
• Journal: PloS one (PLoS One) Vol. 5 Issue 3 Pg. e9690 (Mar 15 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20300619 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Brain-Derived Neurotrophic Factor
• Cytokines
• Interleukin-6
• Nerve Growth Factors
• Nerve Growth Factor
• p38 Mitogen-Activated Protein Kinases

Topics

• Bone Marrow Cells (cytology)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cytokines (metabolism)
• Enzyme-Linked Immunosorbent Assay (methods)
• Flow Cytometry (methods)
• Humans
• Interleukin-6 (biosynthesis, metabolism)
• MAP Kinase Signaling System
• Nerve Growth Factor (metabolism)
• Nerve Growth Factors (metabolism)
• Oligonucleotide Array Sequence Analysis
• Phosphorylation
• Reverse Transcriptase Polymerase Chain Reaction
• Stromal Cells (cytology)
• p38 Mitogen-Activated Protein Kinases (metabolism)