TSLP Induces Mast Cell Development and Aggravates Allergic Reactions through the Activation of MDM2 and STAT6

Abstract

Thymic stromal lymphopoietin (TSLP) is known to promote T helper type 2 cell-associated inflammation. Mast cells are major effector cells in allergic inflammatory responses. We noted that the population and maturation of mast cells were reduced in TSLP-deficient mice (TSLP-/-). Thus, we hypothesized that TSLP might affect mast cell development. We found that TSLP induced the proliferation and differentiation of mast cells from bone marrow progenitors. TSLP-induced mast cell proliferation was abolished by depletion of mouse double minute 2 (MDM2) and signal transducers and activators of transcription 6 (STAT6), as an upstream activator of MDM2. TSLP-/-, in particular, had a considerable deficit in the expression of MDM2 and STAT6. Also, the TSLP deficiency attenuated mast cell-mediated allergic reactions through the downregulation of STAT6 and MDM2. In an antibody microarray chip analysis, MDM2 expression was increased in atopic dermatitis patients. These observations indicate that TSLP is a factor for mast cell development, and that it aggravates mast cell-mediated immune responses.

The Complex Type 2 Endotype in Allergy and Asthma: From Laboratory to Bedside

“…Innate cytokines such as IL-33 and TSLP modulate the mast cell phenotype [50], while type 2 cytokines promote a particular phenotype of smooth muscle cells in asthma and influence permissiveness of epithelium for allergens and of the endothelium for the recruitment of inflammatory cells to inflamed tissues and are involved in the production of mucus [51].…”

Thymic Stromal Lymphopoietin Controls Prostaglandin D2 Generation in Aspirin-Exacerbated Respiratory Disease

“…Remarkably, the levels of TSLP mRNA expression by nasal polyps from AERD patients correlated with polyp CPA3 and hPGDS transcript expression (Fig 5, A and B), as well as with baseline uPGD-M (Fig 5, C) and TX-M (not shown), but not with uLTE 4 . The correlation between TSLP mRNA, mast cell markers, and PGD 2 in vivo suggests a spectrum of AERD pathophysiology that could reflect some combination of inductive effects of TSLP on mast cell markers or the promotion of mast cell proliferation and/or survival by TSLP as suggested by mouse studies (52). Additionally, tissue mast cells promote TSLP expression in a model of allergic rhinitis (53), suggesting that the relationship between mast cells and TSLP in the tissue may be bilateral.…”

“…Among many cellular targets, TSLP facilitates mast cell development in vivo (52) and mast cell activation in vitro (14). Since TSLP is strongly expressed by nasal polyps (10, 11), we focused on its potential role as a driver of PGD 2 generation, both in vivo and in vitro.…”

IL-33 and Thymic Stromal Lymphopoietin in mast cell functions

“…IL-33 promotes mast cell survival through up regulation of the prosurvival protein Bcl-XL . Similar to IL-33, TSLP also induces MC proliferation in both human and murine MCs through activation of MDM2 that is considered as a negative regulator of p53 (Han et al, 2014). This pathway is further governed through STAT 6 dependent manner.…”

“…Several growth factors and cytokines have been demonstrated to be critical for mast cell growth, development and differentiation, including SCF, IL-6 and IL-9 (Hu et al, 2007;Jamur and Oliver, 2011;Saito et al, 1996). TSLP plays an important role in the maturation of MCs (Han et al, 2014). Mast cells from TSLP À / À mice show reduction in number, size and density of granules.…”