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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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Induction of TSLP production by primary human airway epithelial cells. (A) SAECs were stimulated as indicated, and the 48-h culture supernatants were tested for their content in TSLP by ELISA. Mean ± SEM (n = 5). (B) Expression of the indicated TLR mRNA in SAECs was determined by real-time PCR. (C) BAF cells (104 cells/well) expressing the human TSLP-R and IL-7Rα chains were cultured in the presence of SAEC supernatants and in the presence or absence of neutralizing anti-TSLP mAb, and their proliferation was assessed after 3 d. One representative of three experiments is shown; mean ± SD of triplicates. (D–F) MCs were cultured in the presence or absence of supernatants of SAECs (50% vol/vol) described in A that were obtained upon stimulation with IL-1α/TNF (D), PGN (E), or polyI:C (F). IL-13 and IL-5 (not depicted) were measured after 24 h of MC stimulation. Mean ± SEM of four to five experiments.
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fig3: Induction of TSLP production by primary human airway epithelial cells. (A) SAECs were stimulated as indicated, and the 48-h culture supernatants were tested for their content in TSLP by ELISA. Mean ± SEM (n = 5). (B) Expression of the indicated TLR mRNA in SAECs was determined by real-time PCR. (C) BAF cells (104 cells/well) expressing the human TSLP-R and IL-7Rα chains were cultured in the presence of SAEC supernatants and in the presence or absence of neutralizing anti-TSLP mAb, and their proliferation was assessed after 3 d. One representative of three experiments is shown; mean ± SD of triplicates. (D–F) MCs were cultured in the presence or absence of supernatants of SAECs (50% vol/vol) described in A that were obtained upon stimulation with IL-1α/TNF (D), PGN (E), or polyI:C (F). IL-13 and IL-5 (not depicted) were measured after 24 h of MC stimulation. Mean ± SEM of four to five experiments.

Mentions: Given that overexpression of TSLP in the airway epithelial cells induces experimental asthma (9), and that TSLP mRNA is overexpressed in the bronchial mucosa of asthmatic patients (7), we attempted to identify stimuli capable of inducing TSLP production by human airway epithelial cells. To this end, primary small airway epithelial cells (SAECs) were stimulated with: (a) a cocktail of IL-1 and TNF to mimic the inflammatory microenvironment, and (b) bacterial peptidoglycan (PGN) and TLR ligands such as lipoteichoic acid (LTA) from Bacillus subtilis, poly I:C (mimicking viral double-stranded RNA), LPS, imiquimod, and CpG. TSLP was produced only in response to the inflammatory cytokines, PGN, LTA, and poly I:C (Fig. 3 A and Fig. S4, which is available at http://www.jem.org/cgi/content/full/jem.20062211/DC1). The failure of SAEC to respond to LPS, imiquimod, and CpG was explained by the lack of expression of the corresponding TLR's mRNA (Fig. 3 B). The supernatant fluids of activated SAECs promoted the TSLP-dependent proliferation of a BAF cell line transfected with the human TSLP receptor complex (Fig. 3 C). Moreover, the low levels of TSLP present in these culture supernatants were sufficient when used together with IL-1/TNF to induce IL-13 and IL-5 production from MCs (Fig. 3, D–F, and not depicted). Native SAEC-derived TSLP was active at much lower concentrations (50–100 pg/ml; see Fig. 3 A) than recombinant TSLP (10 ng/ml) used as a positive control (Fig. 3 D). This finding suggested that activated SAECs may produce additional factors that act to co-stimulate the response of MCs to TSLP; alternatively, it could reflect a difference in the intrinsic activity of native and recombinant TSLP. It is of note that SAECs stimulated with cytokines, PGN, or polyI:C did not produce detectable IL-5 or IL-13. Moreover, PGN or polyI:C induced the production of very low (<70 pg/ml) or undetectable levels of IL-5 or IL-13 by MCs, even when used together with IL-1/TNF. The observation that bacterial and viral products induce TSLP production by SAEC may be related to the well-documented aggravating role of infection in allergic as well as intrinsic bronchial asthma. For example, 60–80% of asthma exacerbations in children and adults are caused by rhinovirus infection (21). Rhinoviruses, like several other single-stranded RNA viruses, synthesize double-stranded RNA during their replication, thereby engaging TLR3 and initiating signaling cascades leading to cytokine production (22). The up-regulation of TSLP by bacterial products is, however, not restricted to airway epithelial cells as it has been shown in intestinal epithelial cells (23). TSLP activation of MCs may also contribute to the aggravation of AD resulting from skin colonization by Staphylococcus aureus (1). Thus, certain bacterial, viral, and nonspecific inflammatory stimuli (IL-1/TNF) may activate airway epithelial cells to produce TSLP in sufficient amounts to stimulate MCs and thereby initiate and/or aggravate allergic inflammation.


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)

Induction of TSLP production by primary human airway epithelial cells. (A) SAECs were stimulated as indicated, and the 48-h culture supernatants were tested for their content in TSLP by ELISA. Mean ± SEM (n = 5). (B) Expression of the indicated TLR mRNA in SAECs was determined by real-time PCR. (C) BAF cells (104 cells/well) expressing the human TSLP-R and IL-7Rα chains were cultured in the presence of SAEC supernatants and in the presence or absence of neutralizing anti-TSLP mAb, and their proliferation was assessed after 3 d. One representative of three experiments is shown; mean ± SD of triplicates. (D–F) MCs were cultured in the presence or absence of supernatants of SAECs (50% vol/vol) described in A that were obtained upon stimulation with IL-1α/TNF (D), PGN (E), or polyI:C (F). IL-13 and IL-5 (not depicted) were measured after 24 h of MC stimulation. Mean ± SEM of four to five experiments.
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Related In: Results  -  Collection

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fig3: Induction of TSLP production by primary human airway epithelial cells. (A) SAECs were stimulated as indicated, and the 48-h culture supernatants were tested for their content in TSLP by ELISA. Mean ± SEM (n = 5). (B) Expression of the indicated TLR mRNA in SAECs was determined by real-time PCR. (C) BAF cells (104 cells/well) expressing the human TSLP-R and IL-7Rα chains were cultured in the presence of SAEC supernatants and in the presence or absence of neutralizing anti-TSLP mAb, and their proliferation was assessed after 3 d. One representative of three experiments is shown; mean ± SD of triplicates. (D–F) MCs were cultured in the presence or absence of supernatants of SAECs (50% vol/vol) described in A that were obtained upon stimulation with IL-1α/TNF (D), PGN (E), or polyI:C (F). IL-13 and IL-5 (not depicted) were measured after 24 h of MC stimulation. Mean ± SEM of four to five experiments.
Mentions: Given that overexpression of TSLP in the airway epithelial cells induces experimental asthma (9), and that TSLP mRNA is overexpressed in the bronchial mucosa of asthmatic patients (7), we attempted to identify stimuli capable of inducing TSLP production by human airway epithelial cells. To this end, primary small airway epithelial cells (SAECs) were stimulated with: (a) a cocktail of IL-1 and TNF to mimic the inflammatory microenvironment, and (b) bacterial peptidoglycan (PGN) and TLR ligands such as lipoteichoic acid (LTA) from Bacillus subtilis, poly I:C (mimicking viral double-stranded RNA), LPS, imiquimod, and CpG. TSLP was produced only in response to the inflammatory cytokines, PGN, LTA, and poly I:C (Fig. 3 A and Fig. S4, which is available at http://www.jem.org/cgi/content/full/jem.20062211/DC1). The failure of SAEC to respond to LPS, imiquimod, and CpG was explained by the lack of expression of the corresponding TLR's mRNA (Fig. 3 B). The supernatant fluids of activated SAECs promoted the TSLP-dependent proliferation of a BAF cell line transfected with the human TSLP receptor complex (Fig. 3 C). Moreover, the low levels of TSLP present in these culture supernatants were sufficient when used together with IL-1/TNF to induce IL-13 and IL-5 production from MCs (Fig. 3, D–F, and not depicted). Native SAEC-derived TSLP was active at much lower concentrations (50–100 pg/ml; see Fig. 3 A) than recombinant TSLP (10 ng/ml) used as a positive control (Fig. 3 D). This finding suggested that activated SAECs may produce additional factors that act to co-stimulate the response of MCs to TSLP; alternatively, it could reflect a difference in the intrinsic activity of native and recombinant TSLP. It is of note that SAECs stimulated with cytokines, PGN, or polyI:C did not produce detectable IL-5 or IL-13. Moreover, PGN or polyI:C induced the production of very low (<70 pg/ml) or undetectable levels of IL-5 or IL-13 by MCs, even when used together with IL-1/TNF. The observation that bacterial and viral products induce TSLP production by SAEC may be related to the well-documented aggravating role of infection in allergic as well as intrinsic bronchial asthma. For example, 60–80% of asthma exacerbations in children and adults are caused by rhinovirus infection (21). Rhinoviruses, like several other single-stranded RNA viruses, synthesize double-stranded RNA during their replication, thereby engaging TLR3 and initiating signaling cascades leading to cytokine production (22). The up-regulation of TSLP by bacterial products is, however, not restricted to airway epithelial cells as it has been shown in intestinal epithelial cells (23). TSLP activation of MCs may also contribute to the aggravation of AD resulting from skin colonization by Staphylococcus aureus (1). Thus, certain bacterial, viral, and nonspecific inflammatory stimuli (IL-1/TNF) may activate airway epithelial cells to produce TSLP in sufficient amounts to stimulate MCs and thereby initiate and/or aggravate allergic inflammation.

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