Journal
BLOOD
Volume 117, Issue 18, Pages 4826-4835Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-12-324038
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Funding
- Cancer Society of Stockholm
- Children's Cancer Foundation
- Juvenile Diabetes Research Foundation
- Karolinska Institutet
- Stockholm City Council
- Swedish Cancer Society
- Swedish Research Council
- Swedish Society of Medicine
- Sven an Ebba-Christina Hagbergs Foundation
- Tobias Foundation
- German Research Foundation
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Mesenchymal stem cells (MSCs) are characterized by their manifold immunomodulatory and regenerative properties. The stress-responsive, cytoprotective, and immunoregulatory molecule heme oxygenase-1 (HO-1) was recently identified as a key contributor for MSC-mediated suppression of alloactivated T cells. As HO-1 has also been implicated in the induction of regulatory T cells (Tregs), we sought to examine its impact on MSC-driven promotion of Tregs. Human MSCs were shown to induce, in a HO-1-dependent fashion, IL-10(+) Tr1 and transforming growth factor-beta(+) Th3 Treg-subsets in allo-and T-cell receptor-activated lymphocytes. Because inflammatory stimuli modulate (license) human MSCs, we were interested in whether an in vitro alloreactive micro-milieu within mixed lymphocyte reactions (MLRs) alters the HO-1 expression. We observed a substantial down-regulation of HO-1 facilitated by yet unidentified soluble factor(s) produced in an MLR, and most probably occurring at the level of its major transcription-factor NF-E2-related factor 2. Interestingly, HO-1 lost its impact regarding suppressiveness, Treg induction, and promotion of IL-10 production for MSCs, which were prelicensed in an MLR environment. Taken together, we show that HO-1 produced by human MSCs beyond its direct suppressive function promotes formation of Tr1 and Th3 Tregs and IL-10 production, functions, which are taken over by other molecules, among them COX-2, after an alloreactive priming. (Blood. 2011; 117(18): 4826-4835)
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