Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

Abstract

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1␤ and TNF-␣ were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo ؊ and A549, and showed that IL-1␤-and TNF-␣-mediated human TSLP promoter activation in these cells was mediated by an upstream NF B site. Mutation of this NF B site abolished activation, as did overexpression of a dominant-negative version of I B kinase (IKK)␤ (a kinase acting on I B, the inhibitor of NF B). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NF B in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NF B site that was also critical for IL-1␤-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1␤ and TNF-␣ regulate human TSLP gene expression in an NF B-dependent manner.proinflammatory cytokine ͉ T helper 2 inflammation ͉ transcriptional regulation T hymic stromal lymphopoietin (TSLP) is a cytokine that was originally identified in culture supernatants of a mouse thymic stromal cell line and has been shown to support the development of pre-B cells to B220 ϩ IgM ϩ immature B cells (1-4). The TSLP receptor complex is a heterodimer that consists of a low-affinity ligand binding chain, the TSLP receptor (TSLPR), and the IL-7 receptor ␣ chain (IL-7R␣) (5, 6). TSLP and TSLPR have also been identified and characterized in humans, and the human TSLP receptor complex has been shown to also be a heterodimer that is composed of the TSLPR and IL-7R␣ chains (7,8). Although the degree of sequence homology between human and mouse TSLP and between human and mouse TSLPR is quite low (43% and 39%, respectively), the expression profiles are similar in the two species, with B cells and CD11c ϩ dendritic cells being the primary cell populations expressing the TSLPR (ref. 9 and S.F.Z. and D. R. J. Rawlings, unpublished results). TSLP is produced primarily by epithelial cells in the lungs, gut, and skin (8). Recent work (e.g., refs. 10 and 11) has shown that TSLP levels are increased at sites of inflammation. For example, lesional skin from patients with atopic dermatitis displayed markedly elevated TSLP expression, whereas uninvolved skin did not (10). Similarly, airway epithelium from asthmatics showed increased TSLP mRNA expression (11) and supported a role for TSLP in promoting T helper 2-type allergic inflammation. CD4 ϩ T cells, primed by TSLP-treated dendritic cells, produce the proallergic cy...

Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis

“…This is consistent with recent in vitro studies, which suggest that TSLP expression in epithelial cells requires proinflammatory cytokines such as TNF-a [11][12][13]. Therefore, it is possible that mast cell-derived inflammatory cytokines including TNF-a generated at the site of allergic rhinitis may play an important role for the induction of TSLP expression in the nasal epithelium.…”

“…Previous studies suggest that TSLP expression in mouse keratinocytes is regulated by vitamin D and retinoic acid signaling [10]. Most recently, TNF-a, IL-1b, and ligands for Toll-like receptors such as LPS were shown to up-regulate TSLP expression via NF-jB pathway in cultured human bronchial epithelial cells and keratinocytes [11][12][13].…”

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

“…Moreover, it is known that, in general, mucosal DC differ from splenic counterparts. It has been proposed that epithelial cells mount a specific microenvironment affecting the phenotype of professional immune cells and soluble factors like TGF-b, nitric oxide (NO), prostaglandins, IL-10 and thymic stromal lymphopoietin (TSLP) were suggested as possible mediators [17][18][19]. However, no detailed analysis of upper airway bronchial epithelial cells and their impact on immune homeostasis of innate and adaptive immunity is available.…”

Similarities and differences in the transcriptional control of expression of the mouse TSLP gene in skin epidermis and intestinal epithelium

“…Collectively, these data illustrate various physiological and pathophysiological roles of TSLP throughout life, thus suggesting that strict spatiotemporal control of TSLP expression is essential for maintaining homeostasis. Our previous studies (1-3), as well as the studies of other groups (17,29), have generated preliminary evidence regarding the mechanisms that control TSLP expression. In the present study, we have performed a detailed analysis of the cisacting regulatory elements that control TSLP transcription in vivo in mouse epidermal keratinocytes and IEC.…”