TNFR1 signaling resistance associated with female stem cell cytokine production is independent of TNFR2-mediated pathways.

Abstract

End-organ ischemia is a common source of patient morbidity and mortality. Stem cell therapy represents a novel treatment modality for ischemic diseases and may aid injured tissues through the release of beneficial paracrine mediators. Female bone marrow mesenchymal stem cells (MSCs) have demonstrated a relative resistance to detrimental TNF receptor 1 (TNFR1) signaling and are thought to be superior to male stem cells in limiting inflammation. However, it is not known whether sex differences exist in TNF receptor 2 (TNFR2)-ablated MSCs. Therefore, we hypothesized that 1) sex differences would be observed in wild-type (WT) and TNFR2-ablated MSC cytokine signaling, and 2) the production of IL-6, VEGF, and IGF-1 in males, but not females, would be mediated through TNFR2. MSCs were harvested from male and female WT and TNFR2 knockout (TNFR2KO) mice and were subsequently exposed to TNF (50 ng/ml) or LPS (100 ng/ml). After 24 h, supernatants were collected and measured for cytokines. TNF and LPS stimulated WT stem cells to produce cytokines, but sex differences were only seen in IL-6 and IGF-1 after TNF stimulation. Ablation of TNFR2 increased VEGF and IGF-1 production in males compared with wild-type, but no difference was observed in females. Female MSCs from TNFR2KOs produced significantly lower levels of VEGF and IGF-1 compared with male TNFR2KOs. The absence of TNFR2 signaling appears to play a greater role in male MSC cytokine production. As a result, male, but not female stem cell cytokine production may be mediated through TNFR2 signaling cascades.

• Authors: Troy A Markel, Paul R Crisostomo, Meijing Wang, Yue Wang, Tim Lahm, Nathan M Novotny, Jiangning Tan, Daniel R Meldrum
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 295 Issue 4 Pg. R1124-30 (Oct 2008) ISSN: 0363-6119 [Print] United States
• PMID: 18685063 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interleukin-6
• Lipopolysaccharides
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Tnfrsf1a protein, mouse
• Tumor Necrosis Factor-alpha
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Insulin-Like Growth Factor I

Topics

• Animals
• Cytokines (metabolism)
• Female
• Insulin-Like Growth Factor I (metabolism)
• Interleukin-6 (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mesenchymal Stem Cells (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Receptors, Tumor Necrosis Factor, Type I (physiology)
• Receptors, Tumor Necrosis Factor, Type II (genetics, physiology)
• Sex Factors
• Signal Transduction (physiology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)