新宝测速6

• Among the members of the IL-10 family of cytokines including IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29, only IL-10 affects mast cell function.
• IL-10 suppresses the production of a pro-inflammatory cytokine, TNF, but enhances the production of IL-6 and IL-13, from mast cells.
• Although IL-10 is considered to be a major cytokine that suppresses inflammation, our results indicate that IL-10 promotes mast cell activation, contributing to the aggravation of allergic diseases.

Mast cells are immune cells found in the mucous membranes of the nose, eyes, respiratory and digestive tracts. They are responsible for host defense against parasites. High levels of IgE receptors are constitutively expressed on the cell membrane of mast cells. IgE, which recognizes antigens of pathogens, binds to these IgE receptors. However, IgE is also produced against allergenic inducers (allergens) such as pollen. When allergens are recognized by IgE that is bound to mast cells, mast cells are activated to eliminate them, resulting in the induction of allergic symptoms such as sneezing, runny nose, and coughing. In other words, if the function of mast cells can be controlled, allergic diseases can be treated.

Interleukins (ILs), which are one of the cytokines, are the signaling molecules for cell-cell communication. IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29 are collectively called as the IL-10 family of cytokines that share amino acid sequence homology with IL-10.

We found that mast cells express the receptors for the members of the IL-10 family of cytokines. Therefore, we hypothesized that one and/or some of the members of the IL-10 family of cytokines may affect mast cell function. When mast cells were cultured in the presence of IgE, they secrete several cytokines such as IL-6, IL-13 and TNF. Under these settings, we examined the role of the members of the IL-10 family of cytokines. Among the members of the IL-10 family of cytokines, we found that only IL-10 can influence the secretion of IL-6, IL-13 and TNF by mast cells.

IL-10 is a well-known cytokine that can suppress inflammation. In fact, the development of certain diseases is known to be treated by the administration of IL-10 in mice. We found that IL-10 can inhibit secretion of TNF, but enhances that of IL-6 and IL-13, from mast cells. After binding of IL-10 to the receptors, various gene expressions are induced through the activation of transcription factors such as STAT1, STAT3 and/or STAT5. Under this situation, the enhancement of IL-6 and IL-13 secretion by IL-10 in mast cells requires both STAT1 and STAT3, but suppression of TNF secretion does not require STAT1 and STAT3, suggesting the involvement of STAT5.

In mice with allergic asthma, IL-10 was reported to suppress airway inflammation, while it worsened airway hypersensitivity (narrowing of bronchi resulting to breathing difficulties). However, the reason why IL-10 makes airway irritability worse has been unknown for a long time. However, IL-13 is a key cytokine to induce airway hypersensitivity. Therefore, IL-10 was suggested to be involved in the enhancement of airway irritability by enhancing IL-13 secretion from mast cells. In addition, it was found that IL-10 enhances IL-6 secretion by mast cells, which leads to excessive activation of Th17 cells (a type of T cells that play a central role in immune cells), which also plays an important role in host defense for pathogens. On the other hand, excessive Th17 cell activation is known to aggravate not only allergic diseases but also various diseases.

Our findings have revealed that IL-10 has two functions in not only suppressing inflammation but also conversely exacerbating it, and that mast cells are involved in both of these functions. Based on these results, we expect that the pathogenesis of allergic diseases, which are intractable, should be further elucidated.

• Journal: Scientific Reports
• Title: IL-10 promotes Th17 cell differentiation by enhancing STAT1-dependent IL-6 production via IgE-stimulated mast cells
• Authors: Takafumi Numata, Masashi Ikutani, Ken Arae, Tatsukuni Ohno, Takayuki Yoshimoto, Katsuko Sudo, Hajime Suto, Ko Okumura, Hirohisa Saito, Kazutoshi Harada, Susumu Nakae
• DOI: 10.1038/s41598-024-77929-y.