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

Troy A. Markel, Paul R. Crisostomo, Meijing Wang, Yue Wang, Tim Lahm, Nathan M. Novotny, Jiangning Tan, Daniel R. Meldrum

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)R1124-R1130
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number4
StatePublished - Oct 2008


  • Estrogen
  • Hormones
  • Sex
  • TNFR1
  • TNFR2

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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