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Combined stimulation with the T helper cell type 2 cytokines interleukin (IL)-4 and IL-10 induces mouse mast cell apoptosis.

Yeatman CF, Jacobs-Helber SM, Mirmonsef P, Gillespie SR, Bouton LA, Collins HA, Sawyer ST, Shelburne CP, Ryan JJ - J. Exp. Med. (2000)

Bottom Line: Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2.Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10.Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia 23284, USA.

ABSTRACT
Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)-antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3-dependent bone marrow-derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3-independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine-mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.

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Stimulation with IL-4+IL-10 induces apoptosis in freshly isolated peritoneal mast cells. Peritoneal mast cells were cultured for 6 d in the indicated cytokines, and assessed for apoptosis by PI staining. Data shown represent the mean percent apoptotic cells of triplicate samples from one of two representative experiments. *P < 0.05.
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Figure 3: Stimulation with IL-4+IL-10 induces apoptosis in freshly isolated peritoneal mast cells. Peritoneal mast cells were cultured for 6 d in the indicated cytokines, and assessed for apoptosis by PI staining. Data shown represent the mean percent apoptotic cells of triplicate samples from one of two representative experiments. *P < 0.05.

Mentions: As shown in Fig. 3, peritoneal mast cells cultured in IL-3+IL-4 or in IL-3+IL-4+IL-10 demonstrated a significant increase in apoptosis compared with cells cultured in IL-3 alone. The total number of cells (viable plus apoptotic, obtained by timed flow cytometer assessment) in each of these culture conditions was remarkably similar, with a minimum of 3, 694 (± 154) observed with cells cultured in IL-3+IL-4+IL-10, and a maximum of 4,719 (± 22) observed with cells cultured in IL-3 alone. These data corroborate our results presented in Fig. 1 and Fig. 2, and further support our theory that costimulation with IL-4+IL-10 leads to apoptosis that limits mast cell expansion.


Combined stimulation with the T helper cell type 2 cytokines interleukin (IL)-4 and IL-10 induces mouse mast cell apoptosis.

Yeatman CF, Jacobs-Helber SM, Mirmonsef P, Gillespie SR, Bouton LA, Collins HA, Sawyer ST, Shelburne CP, Ryan JJ - J. Exp. Med. (2000)

Stimulation with IL-4+IL-10 induces apoptosis in freshly isolated peritoneal mast cells. Peritoneal mast cells were cultured for 6 d in the indicated cytokines, and assessed for apoptosis by PI staining. Data shown represent the mean percent apoptotic cells of triplicate samples from one of two representative experiments. *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195863&req=5

Figure 3: Stimulation with IL-4+IL-10 induces apoptosis in freshly isolated peritoneal mast cells. Peritoneal mast cells were cultured for 6 d in the indicated cytokines, and assessed for apoptosis by PI staining. Data shown represent the mean percent apoptotic cells of triplicate samples from one of two representative experiments. *P < 0.05.
Mentions: As shown in Fig. 3, peritoneal mast cells cultured in IL-3+IL-4 or in IL-3+IL-4+IL-10 demonstrated a significant increase in apoptosis compared with cells cultured in IL-3 alone. The total number of cells (viable plus apoptotic, obtained by timed flow cytometer assessment) in each of these culture conditions was remarkably similar, with a minimum of 3, 694 (± 154) observed with cells cultured in IL-3+IL-4+IL-10, and a maximum of 4,719 (± 22) observed with cells cultured in IL-3 alone. These data corroborate our results presented in Fig. 1 and Fig. 2, and further support our theory that costimulation with IL-4+IL-10 leads to apoptosis that limits mast cell expansion.

Bottom Line: Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2.Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10.Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia 23284, USA.

ABSTRACT
Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)-antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3-dependent bone marrow-derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3-independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine-mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.

Show MeSH
Related in: MedlinePlus