The intestinal epithelial barrier plays a critical role in the mucosal immunity. However, it remains largely unknown how the epithelial barrier is maintained after damage. Here we show that growth factor FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium. FGF2 or IL-17 deficiency resulted in impaired epithelial proliferation, increased pro-inflammatory microbiota outgrowth, and consequently worse pathology in a DSS-induced colitis model. The dysregulated microbiota in the model induced transforming growth factor beta 1 (TGFβ1) expression, which in turn induced FGF2 expression mainly in regulatory T cells. Act1, an essential adaptor in IL-17 signaling, suppressed FGF2-induced ERK activation through binding to adaptor molecule GRB2 to interfere with its association with guanine nucleotide exchange factor SOS1. Act1 preferentially bound to IL-17 receptor complex, releasing its suppressive effect on FGF2 signaling. Thus, microbiota-driven FGF2 and IL-17 cooperate to repair the damaged intestinal epithelium through Act1-mediated direct signaling cross-talk.

Although the microbiota has been shown to drive production of interleukin-17A (IL-17A) from T helper 17 cells to promote cell proliferation and tumor growth in colorectal cancer, the molecular mechanisms for microbiota-mediated regulation of tumorigenesis are largely unknown. Here, we found that the innate-like cytokine IL-17C was upregulated in human colorectal cancers and in mouse intestinal tumor models. Alterations in the microbiota drove IL-17C upregulation specifically in intestinal epithelial cells (IECs) through Toll-like receptor (TLR)-MyD88-dependent signaling during intestinal tumorigenesis. Microbiota-driven IL-17C induced Bcl-2 and Bcl-xL expression in IECs in an autocrine manner to promote cell survival and tumorigenesis in both chemically induced and spontaneous intestinal tumor models. Thus, IL-17C promotes cancer development by increasing IEC survival, and the microbiota can mediate cancer pathogenesis through regulation of IL-17C.

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By binding to the interleukin 17 receptor (IL-17R), TRAF3 blocks formation of the IL-17R–Act1–TRAF6 complex and inhibits downstream signaling.

In conclusion, our data suggest that human IL-6, IL-17, IL-1β, and TNF-α significantly activate PAECs and are likely to promote inflammation and coagulation reaction in response to xenograft.

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The major limitation of organ transplantation is the shortage of available organs from deceased human donors which leads to the deaths of thousands of patients each year.Xenotransplantation is considered to be an effective way to resolve the problem.

CD4(+) T helper cells are classical but constantly reinterpreted T-cell subset, playing critical roles in a diverse range of inflammatory responses or diseases. Depending on the cytokines they release and the immune responses they mediate, CD4(+) T cells are classically divided into two major cell populations: Th1 and Th2 cells. However, recent studies challenged this Th1/Th2 paradigm by discovering several T-helper cell subsets with specific differentiation program and functions, including Th17 cells, Treg cells, and Tfh cells. In this chapter, we summarize the current understanding and recent progresses on the Th17 lineage differentiation and its effector impacts on variety of inflammatory responses or disease pathogenesis.