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The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

Rossi F, Bernardo ME, Bellini G, Luongo L, Conforti A, Manzo I, Guida F, Cristino L, Imperatore R, Petrosino S, Nobili B, Di Marzo V, Locatelli F, Maione S - PLoS ONE (2013)

Bottom Line: Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses.Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated.We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

View Article: PubMed Central - PubMed

Affiliation: Department of Women, Child and General and Specialistic Surgery, Second University of Naples, Naples, Italy ; Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy.

ABSTRACT
Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

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Stimulation of the CB2 receptor partially reverses the LPS-induced modulation of pro- and anti- inflammatory cytokines in hMSCs.The release of the anti-inflammatory IL-10 (A) and of the pro-inflammatory IL-1β (B), IL-8 (C) and IL-17 (D), as well as of IL-6 (E), TNF-α (F) and INF-γ (G) from MSCs have been investigated through a multi-ELISA assay. IL-10 secretion by MSC cells was significantly reduced in response to 500 ng/ml LPS, while IL-1β, IL-8 and IL-17 were significantly increased. The treatment with the CB2 agonist JWH.-133 1 µM was able to revert the LPS-induced effect. The CB2 stimulation decreased the release of all the cytokines, even of the anti-inflammatory IL-10, thus was conversely shown to be up-regulated in total cellular lysates both at P6 and after CB2 stimulation, as revealed by the western blot included in the A1 inset. The release of IL-6, TNF-α and INF-γ by MSC cells, undetectable at basal condition, was significantly increased in response to 500 ng/ml LPS. The treatment with the CB2 agonist JWH-133 1 µM was able to fully revert the LPS-induced effect. Mean concentration ± SD (pg/ml) for all the cytokines from triplicate cultures is shown. A t-test has been used for statistical analysis. p<0.05 has been considered statistically significant.
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pone-0080022-g004: Stimulation of the CB2 receptor partially reverses the LPS-induced modulation of pro- and anti- inflammatory cytokines in hMSCs.The release of the anti-inflammatory IL-10 (A) and of the pro-inflammatory IL-1β (B), IL-8 (C) and IL-17 (D), as well as of IL-6 (E), TNF-α (F) and INF-γ (G) from MSCs have been investigated through a multi-ELISA assay. IL-10 secretion by MSC cells was significantly reduced in response to 500 ng/ml LPS, while IL-1β, IL-8 and IL-17 were significantly increased. The treatment with the CB2 agonist JWH.-133 1 µM was able to revert the LPS-induced effect. The CB2 stimulation decreased the release of all the cytokines, even of the anti-inflammatory IL-10, thus was conversely shown to be up-regulated in total cellular lysates both at P6 and after CB2 stimulation, as revealed by the western blot included in the A1 inset. The release of IL-6, TNF-α and INF-γ by MSC cells, undetectable at basal condition, was significantly increased in response to 500 ng/ml LPS. The treatment with the CB2 agonist JWH-133 1 µM was able to fully revert the LPS-induced effect. Mean concentration ± SD (pg/ml) for all the cytokines from triplicate cultures is shown. A t-test has been used for statistical analysis. p<0.05 has been considered statistically significant.

Mentions: The ELISA assay revealed that LPS induced a reduction in the release of the anti-inflammatory cytokine IL-10 (Fig. 4A), and, conversely, a significant enhancement of the pro-inflammatory cytokines IL-1β (Fig. 4B), IL-8 (Fig. 4C) and IL-17 (Fig. 4D).


The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

Rossi F, Bernardo ME, Bellini G, Luongo L, Conforti A, Manzo I, Guida F, Cristino L, Imperatore R, Petrosino S, Nobili B, Di Marzo V, Locatelli F, Maione S - PLoS ONE (2013)

Stimulation of the CB2 receptor partially reverses the LPS-induced modulation of pro- and anti- inflammatory cytokines in hMSCs.The release of the anti-inflammatory IL-10 (A) and of the pro-inflammatory IL-1β (B), IL-8 (C) and IL-17 (D), as well as of IL-6 (E), TNF-α (F) and INF-γ (G) from MSCs have been investigated through a multi-ELISA assay. IL-10 secretion by MSC cells was significantly reduced in response to 500 ng/ml LPS, while IL-1β, IL-8 and IL-17 were significantly increased. The treatment with the CB2 agonist JWH.-133 1 µM was able to revert the LPS-induced effect. The CB2 stimulation decreased the release of all the cytokines, even of the anti-inflammatory IL-10, thus was conversely shown to be up-regulated in total cellular lysates both at P6 and after CB2 stimulation, as revealed by the western blot included in the A1 inset. The release of IL-6, TNF-α and INF-γ by MSC cells, undetectable at basal condition, was significantly increased in response to 500 ng/ml LPS. The treatment with the CB2 agonist JWH-133 1 µM was able to fully revert the LPS-induced effect. Mean concentration ± SD (pg/ml) for all the cytokines from triplicate cultures is shown. A t-test has been used for statistical analysis. p<0.05 has been considered statistically significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842278&req=5

pone-0080022-g004: Stimulation of the CB2 receptor partially reverses the LPS-induced modulation of pro- and anti- inflammatory cytokines in hMSCs.The release of the anti-inflammatory IL-10 (A) and of the pro-inflammatory IL-1β (B), IL-8 (C) and IL-17 (D), as well as of IL-6 (E), TNF-α (F) and INF-γ (G) from MSCs have been investigated through a multi-ELISA assay. IL-10 secretion by MSC cells was significantly reduced in response to 500 ng/ml LPS, while IL-1β, IL-8 and IL-17 were significantly increased. The treatment with the CB2 agonist JWH.-133 1 µM was able to revert the LPS-induced effect. The CB2 stimulation decreased the release of all the cytokines, even of the anti-inflammatory IL-10, thus was conversely shown to be up-regulated in total cellular lysates both at P6 and after CB2 stimulation, as revealed by the western blot included in the A1 inset. The release of IL-6, TNF-α and INF-γ by MSC cells, undetectable at basal condition, was significantly increased in response to 500 ng/ml LPS. The treatment with the CB2 agonist JWH-133 1 µM was able to fully revert the LPS-induced effect. Mean concentration ± SD (pg/ml) for all the cytokines from triplicate cultures is shown. A t-test has been used for statistical analysis. p<0.05 has been considered statistically significant.
Mentions: The ELISA assay revealed that LPS induced a reduction in the release of the anti-inflammatory cytokine IL-10 (Fig. 4A), and, conversely, a significant enhancement of the pro-inflammatory cytokines IL-1β (Fig. 4B), IL-8 (Fig. 4C) and IL-17 (Fig. 4D).

Bottom Line: Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses.Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated.We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

View Article: PubMed Central - PubMed

Affiliation: Department of Women, Child and General and Specialistic Surgery, Second University of Naples, Naples, Italy ; Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy.

ABSTRACT
Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

Show MeSH
Related in: MedlinePlus