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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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MC activation by skin-derived TSLP. (A) MCs were cultured with or without lesional or nonlesional skin fragments from AD patients in the presence of IL-1β/TNF with or without neutralizing mAb to TSLP. IL-13 and IL-5 (not depicted) were measured in the supernatants after 24 h of culture. (B) TSLP mRNA was assessed in the lesional and nonlesional skin of AD patients by real-time PCR. (C) Skin explants from nonallergic patients undergoing plastic surgery were minced and cultured for 24 h. Their cell-free culture supernatants (50% vol/vol) were used to stimulate MCs in the presence of IL-1β/TNF with or without mAb to TSLP and TSLP-R or isotype control. IL-13 was measured after 24 h of culture. One representative of three experiments is shown; mean ± SD of triplicates. (D) TSLP mRNA was assessed on freshly isolated or cultured for 24-h skin explants. (E) TSLP protein was measured in the supernatant fluids of these cultures. One representative of three experiments is shown; mean ± SD of triplicates.
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fig4: MC activation by skin-derived TSLP. (A) MCs were cultured with or without lesional or nonlesional skin fragments from AD patients in the presence of IL-1β/TNF with or without neutralizing mAb to TSLP. IL-13 and IL-5 (not depicted) were measured in the supernatants after 24 h of culture. (B) TSLP mRNA was assessed in the lesional and nonlesional skin of AD patients by real-time PCR. (C) Skin explants from nonallergic patients undergoing plastic surgery were minced and cultured for 24 h. Their cell-free culture supernatants (50% vol/vol) were used to stimulate MCs in the presence of IL-1β/TNF with or without mAb to TSLP and TSLP-R or isotype control. IL-13 was measured after 24 h of culture. One representative of three experiments is shown; mean ± SD of triplicates. (D) TSLP mRNA was assessed on freshly isolated or cultured for 24-h skin explants. (E) TSLP protein was measured in the supernatant fluids of these cultures. One representative of three experiments is shown; mean ± SD of triplicates.

Mentions: Because TSLP protein is reportedly overexpressed at the lesional sites of AD (3), we examined the possible involvement of TSLP-induced MC activation in this disease. To this end, biopsy fragments of lesional and nonlesional skin from AD patients were examined for their ability to directly stimulate MCs in co-culture experiments. As seen in Fig. 4 A, lesional skin induced IL-13 production by MCs in a TSLP-dependent manner, whereas nonlesional skin from the same patients was less active. Moreover, TSLP mRNA levels were higher in biopsy fragments from lesional than nonlesional skin (Fig. 4 B). The finding that nonlesional skin was active on MCs led us to test whether TSLP production was a feature of atopy or was induced by the physical trauma of the skin resulting from the biopsy. The latter possibility was supported by the finding that skin fragments of normal individuals released TSLP protein after 24 h of culture in sufficient quantities to stimulate MCs (Fig. 4 C). No such activity was elicited by supernatant fluids collected after 1 h of skin culture. Because normal skin reportedly does not express detectable TSLP protein (3), the data suggest that TSLP was induced during the culture of skin explants. This view was supported by the finding of increasing TSLP mRNA and protein expression over time in the skin cultures (Fig. 4, D and E). A similar result was obtained in experiments examining TSLP mRNA and protein expression over time in mouse skin punch biopsies (not depicted). The production of TSLP together with several proinflammatory cytokines after physical trauma may account for the aggravating role of scratching in atopic eczema (1).


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)

MC activation by skin-derived TSLP. (A) MCs were cultured with or without lesional or nonlesional skin fragments from AD patients in the presence of IL-1β/TNF with or without neutralizing mAb to TSLP. IL-13 and IL-5 (not depicted) were measured in the supernatants after 24 h of culture. (B) TSLP mRNA was assessed in the lesional and nonlesional skin of AD patients by real-time PCR. (C) Skin explants from nonallergic patients undergoing plastic surgery were minced and cultured for 24 h. Their cell-free culture supernatants (50% vol/vol) were used to stimulate MCs in the presence of IL-1β/TNF with or without mAb to TSLP and TSLP-R or isotype control. IL-13 was measured after 24 h of culture. One representative of three experiments is shown; mean ± SD of triplicates. (D) TSLP mRNA was assessed on freshly isolated or cultured for 24-h skin explants. (E) TSLP protein was measured in the supernatant fluids of these cultures. One representative of three experiments is shown; mean ± SD of triplicates.
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Related In: Results  -  Collection

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fig4: MC activation by skin-derived TSLP. (A) MCs were cultured with or without lesional or nonlesional skin fragments from AD patients in the presence of IL-1β/TNF with or without neutralizing mAb to TSLP. IL-13 and IL-5 (not depicted) were measured in the supernatants after 24 h of culture. (B) TSLP mRNA was assessed in the lesional and nonlesional skin of AD patients by real-time PCR. (C) Skin explants from nonallergic patients undergoing plastic surgery were minced and cultured for 24 h. Their cell-free culture supernatants (50% vol/vol) were used to stimulate MCs in the presence of IL-1β/TNF with or without mAb to TSLP and TSLP-R or isotype control. IL-13 was measured after 24 h of culture. One representative of three experiments is shown; mean ± SD of triplicates. (D) TSLP mRNA was assessed on freshly isolated or cultured for 24-h skin explants. (E) TSLP protein was measured in the supernatant fluids of these cultures. One representative of three experiments is shown; mean ± SD of triplicates.
Mentions: Because TSLP protein is reportedly overexpressed at the lesional sites of AD (3), we examined the possible involvement of TSLP-induced MC activation in this disease. To this end, biopsy fragments of lesional and nonlesional skin from AD patients were examined for their ability to directly stimulate MCs in co-culture experiments. As seen in Fig. 4 A, lesional skin induced IL-13 production by MCs in a TSLP-dependent manner, whereas nonlesional skin from the same patients was less active. Moreover, TSLP mRNA levels were higher in biopsy fragments from lesional than nonlesional skin (Fig. 4 B). The finding that nonlesional skin was active on MCs led us to test whether TSLP production was a feature of atopy or was induced by the physical trauma of the skin resulting from the biopsy. The latter possibility was supported by the finding that skin fragments of normal individuals released TSLP protein after 24 h of culture in sufficient quantities to stimulate MCs (Fig. 4 C). No such activity was elicited by supernatant fluids collected after 1 h of skin culture. Because normal skin reportedly does not express detectable TSLP protein (3), the data suggest that TSLP was induced during the culture of skin explants. This view was supported by the finding of increasing TSLP mRNA and protein expression over time in the skin cultures (Fig. 4, D and E). A similar result was obtained in experiments examining TSLP mRNA and protein expression over time in mouse skin punch biopsies (not depicted). The production of TSLP together with several proinflammatory cytokines after physical trauma may account for the aggravating role of scratching in atopic eczema (1).

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