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. 2014 Jan 14:15:1.
doi: 10.1186/1471-2172-15-1.

Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome

Hani Kim, Ilyse Darwish, Maria-Fernanda Monroy, Darwin J Prockop, W Conrad Liles, Kevin C Kain  1
Affiliations

Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome

Hani Kim et al. BMC Immunol. .

Abstract

Background: Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS.

Methods: Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 μg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 μg) in HLA-DR4 transgenic mice.

Results: Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS.

Conclusions: Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.

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Figures

Figure 1
Figure 1
Differentiation of Passage 3 hMSCs into adipocytes, osteocytes and chondrocytes. Phase-contrast microscopy images of: adipogenic differentiation (A-C; Oil Red O staining of undifferentiated mMSCs (A) and differentiated adipocytes (C); unstained differentiated adipocytes (B)); osteogenic differentiation (D-F; Alizarin Red S staining of undifferentiated mMSCs (D) and differentiated osteocytes (F); unstained differentiated osteocytes (E)). (G-I) Alcian Blue staining of cytospins prepared from undifferentiated mMSCs (G) and differentiated chondrocytes (H); phase-contrast microscopy image of the Alcian Blue stained cytopin of differentiated chondrocytes (I).
Figure 2
Figure 2
hMSCs suppress proinflammatory cytokine production induced by SEB in vivo. (A-D) Levels of IFNγ (A), IL-2 (B), IL-6 (C) and TNF (D) were measured from serum collected at the indicated times after SEB was injected in mice pre-treated with hMSCs (white) or PBS as a control (black). Each bar represents a mean + SEM. Statistical differences between the PBS and hMSC groups were assessed by 2-way ANOVA (p=0.6322 (A), p=0.0014 (B), p=0.0011 (C), p=0.0149 (D), n=5/group/time). Data are representative of two independent experiments. (E-H) Serum levels of IFNγ (E), IL-2 (F) and IL-6 (G) and TNF (H) at 2hr post-SEB injection were compared between PBS and hMSC groups. Statistical differences were assessed by the Mann–Whitney test. Data represent a pooled result of two independent experiments. n.s.=not significant.
Figure 3
Figure 3
Neither hMSCs nor TSG-6 improve survival in experimental fatal staphylococcal TSS. Kaplan Meyer survival curves are shown for HLA-DR4 mice which were treated with 2.5×105 hMSCs (A, dotted line, diamond), human recombinant TSG-6 (B, dotted line, diamond) or PBS (A, B solid, square) one hour prior to the induction of TSS. Statistical differences were assessed by log-rank test (p=0.7327 (A), p=0.7258 (B), n=20-22/group). Data represent a pooled result from two independent experiments.
Figure 4
Figure 4
Differentiation of Passage 6 mMSCs into adipocytes, osteocytes and chondrocytes. Phase-contrast microscopy images of: adipogenic differentiation (A-C; Oil Red O staining of undifferentiated mMSCs (A) and differentiated adipocytes (C); unstained differentiated adipocytes (B)); osteogenic differentiation (D-F; Alizarin Red S staining of undifferentiated mMSCs (D) and differentiated osteocytes (F); unstained differentiated osteocytes (E)). (G-I) Alcian Blue staining of cytospins prepared from undifferentiated mMSCs (G) and differentiated chondrocytes (H); phase-contrast microscopy image of the Alcian Blue stained cytospin of differentiated chondrocytes (I).
Figure 5
Figure 5
mMSCs fail to improve survival in experimental fatal staphylococcal TSS with or without pre-treatment with IFNγ. Kaplan Meyer survival curves are shown for HLA-DR4 mice which were treated with 2.5×105 untreated mMSCs (A, dotted line, diamond), IFNγ-treated mMSCs (B, dotted line, diamond) or PBS (A, B solid line, square) one hour prior the induction of TSS. Statistical differences were assessed by log-rank test (p=0.4280 (A), p=0.2184 (B), n=20-22/group). Data represent a pooled result from two independent experiments.
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