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Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells.

Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G - J. Exp. Med. (2007)

Bottom Line: Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system.We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs).Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory on Allergy, CHUM Research Center, Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada.

ABSTRACT
Compelling evidence suggests that the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell-mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

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TSLP-stimulated secretion of cytokines and chemokines by MCs. Cytokine (A) and chemokine (B) secretion by MCs (105 cells/ml) stimulated for 24 h with 10 ng/ml IL-1β/TNF or/and TSLP was assessed by ELISA. Mean ± SEM (n = 11).
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fig2: TSLP-stimulated secretion of cytokines and chemokines by MCs. Cytokine (A) and chemokine (B) secretion by MCs (105 cells/ml) stimulated for 24 h with 10 ng/ml IL-1β/TNF or/and TSLP was assessed by ELISA. Mean ± SEM (n = 11).

Mentions: Typically, IgE-dependent MC activation results in the liberation of granule-associated mediators such as histamine and tryptase, the synthesis of lipid mediators such as PGD2 and LTC4, and the synthesis of a wide spectrum of cytokines and chemokines. MC activation is not a “yes or no” phenomenon, and similar to several other MC activators (for review see reference 16), TSLP did not induce MC degranulation or the release of lipid mediators (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20062211/DC1), even when used at various concentrations with or without IL-1/TNF. In contrast, very high levels of the proinflammatory cytokines/chemokines IL-5, IL-13, IL-6, GM-CSF, CXCL8, and CCL1 were released after 24 h of MC stimulation by TSLP in the presence of IL-1/TNF (Fig. 2). Regardless of the experimental conditions, the following cytokines/chemokines, including IL-4, IL-9, IL-12, IL-15, IFN-γ, CXCL10, CCL24, CCL17, CCL13, CCL22, and CCL5, were either undetectable or present at very low levels (<70 pg/ml). Stimulation of MCs with IL-1/TNF induced the release of high levels of CCL2 and CCL3, and this was not affected by TSLP (CCL2: 3,512 ± 346 pg/ml vs. 3,912 ± 669 pg/ml with TSLP; CCL3: 3,921 ± 725 pg/ml vs. 3,415 ± 483 pg/ml with TSLP). Collectively, these data indicated that in inflammatory conditions mimicked by the presence of IL-1 and TNF, TSLP is a potent activator of MCs leading to the production of very high levels of proinflammatory Th2 cytokines and chemokines that are reportedly sufficient to induce and maintain an allergic phenotype. For instance, the perfusion of IL-13 induces an asthma-like phenotype characterized by eosinophilic inflammation, bronchial hyperreactivity, and airway remodeling (17). Given the important role of TNF in severe asthma (18), it is of note that this cytokine was released at high levels by MCs stimulated with IL-1 and TSLP (not depicted). The proinflammatory activity of TSLP was further indicated by its suppressive activity on the production of TGF-β. This finding together with the observation that TGF-β inhibits the response to TSLP (Fig. S3) suggests a negative regulatory feedback between these two cytokines. In contrast to TGF-β, the production of IL-10 was enhanced by TSLP and exogenous IL-10 did not affect the MC response to TSLP (not depicted). IL-10 is overexpressed in the lesional skin of AD patients (19) where it inhibits the production of antimicrobial peptides, thereby contributing to the microbial colonization of the skin (20). Because IgE/anti-IgE–stimulated MCs reportedly expressed TSLP mRNA (5), we have examined TSLP expression in response to IL-1/TNF used alone or together with exogenous TSLP. TSLP was not induced in these conditions as revealed by: (a) the absence of TSLP protein in the culture supernatants of IL-1/TNF-stimulated MCs (<7 pg/ml), (b) the lack of effect of blocking anti-TSLP mAb on chemokine production by IL-1/TNF-stimulated MCs, and (c) quantitative real-time RT-PCR analysis of TSLP mRNA expression (Fig. S1, A and B). The potential clinical significance of the findings that TSLP-stimulated MCs produce high levels of proinflammatory Th2 cytokines and chemokines is supported by the recently reemphasized concept that MCs have a central role in the development and maintenance of allergic diseases (for review see reference 13).


Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells.

Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G - J. Exp. Med. (2007)

TSLP-stimulated secretion of cytokines and chemokines by MCs. Cytokine (A) and chemokine (B) secretion by MCs (105 cells/ml) stimulated for 24 h with 10 ng/ml IL-1β/TNF or/and TSLP was assessed by ELISA. Mean ± SEM (n = 11).
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Related In: Results  -  Collection

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fig2: TSLP-stimulated secretion of cytokines and chemokines by MCs. Cytokine (A) and chemokine (B) secretion by MCs (105 cells/ml) stimulated for 24 h with 10 ng/ml IL-1β/TNF or/and TSLP was assessed by ELISA. Mean ± SEM (n = 11).
Mentions: Typically, IgE-dependent MC activation results in the liberation of granule-associated mediators such as histamine and tryptase, the synthesis of lipid mediators such as PGD2 and LTC4, and the synthesis of a wide spectrum of cytokines and chemokines. MC activation is not a “yes or no” phenomenon, and similar to several other MC activators (for review see reference 16), TSLP did not induce MC degranulation or the release of lipid mediators (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20062211/DC1), even when used at various concentrations with or without IL-1/TNF. In contrast, very high levels of the proinflammatory cytokines/chemokines IL-5, IL-13, IL-6, GM-CSF, CXCL8, and CCL1 were released after 24 h of MC stimulation by TSLP in the presence of IL-1/TNF (Fig. 2). Regardless of the experimental conditions, the following cytokines/chemokines, including IL-4, IL-9, IL-12, IL-15, IFN-γ, CXCL10, CCL24, CCL17, CCL13, CCL22, and CCL5, were either undetectable or present at very low levels (<70 pg/ml). Stimulation of MCs with IL-1/TNF induced the release of high levels of CCL2 and CCL3, and this was not affected by TSLP (CCL2: 3,512 ± 346 pg/ml vs. 3,912 ± 669 pg/ml with TSLP; CCL3: 3,921 ± 725 pg/ml vs. 3,415 ± 483 pg/ml with TSLP). Collectively, these data indicated that in inflammatory conditions mimicked by the presence of IL-1 and TNF, TSLP is a potent activator of MCs leading to the production of very high levels of proinflammatory Th2 cytokines and chemokines that are reportedly sufficient to induce and maintain an allergic phenotype. For instance, the perfusion of IL-13 induces an asthma-like phenotype characterized by eosinophilic inflammation, bronchial hyperreactivity, and airway remodeling (17). Given the important role of TNF in severe asthma (18), it is of note that this cytokine was released at high levels by MCs stimulated with IL-1 and TSLP (not depicted). The proinflammatory activity of TSLP was further indicated by its suppressive activity on the production of TGF-β. This finding together with the observation that TGF-β inhibits the response to TSLP (Fig. S3) suggests a negative regulatory feedback between these two cytokines. In contrast to TGF-β, the production of IL-10 was enhanced by TSLP and exogenous IL-10 did not affect the MC response to TSLP (not depicted). IL-10 is overexpressed in the lesional skin of AD patients (19) where it inhibits the production of antimicrobial peptides, thereby contributing to the microbial colonization of the skin (20). Because IgE/anti-IgE–stimulated MCs reportedly expressed TSLP mRNA (5), we have examined TSLP expression in response to IL-1/TNF used alone or together with exogenous TSLP. TSLP was not induced in these conditions as revealed by: (a) the absence of TSLP protein in the culture supernatants of IL-1/TNF-stimulated MCs (<7 pg/ml), (b) the lack of effect of blocking anti-TSLP mAb on chemokine production by IL-1/TNF-stimulated MCs, and (c) quantitative real-time RT-PCR analysis of TSLP mRNA expression (Fig. S1, A and B). The potential clinical significance of the findings that TSLP-stimulated MCs produce high levels of proinflammatory Th2 cytokines and chemokines is supported by the recently reemphasized concept that MCs have a central role in the development and maintenance of allergic diseases (for review see reference 13).

Bottom Line: Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system.We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs).Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory on Allergy, CHUM Research Center, Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada.

ABSTRACT
Compelling evidence suggests that the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell-mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

Show MeSH
Related in: MedlinePlus