Forced Expression of Murine IL-17E Induces Growth Retardation, Jaundice, a Th2-Biased Response, and Multiorgan Inflammation in Mice

Abstract

IL-17 is a proinflammatory cytokine, and its in vivo expression induces neutrophilia in mice. IL-17E is a recently described member of an emerging family of IL-17-related cytokines. IL-17E has been shown to bind IL-17Rh1, a protein distantly related to the IL-17R, suggesting that IL-17E probably possesses unique biological functions. In this study, we have identified the murine ortholog of IL-17E and developed transgenic mice to characterize its actions in vivo. Biological consequences of overexpression of murine (m)IL-17E, both unique to IL-17E and similar to IL-17, were revealed. Exposure to mIL-17E resulted in a Th2-biased response, characterized by eosinophilia, increased serum IgE and IgG1, and a Th2 cytokine profile including elevated serum levels of IL-13 and IL-5 and elevated gene expression of IL-4, IL-5, IL-10, and IL-13 was observed in many tissues. Increased gene expression of IFN-γ in several tissues and elevated serum TNF-α were also noted. In addition, IL-17E induces G-CSF production in vitro and mIL-17E-transgenic mice had increased serum G-CSF and exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to mIL-17E elicited pathological changes in multiple tissues, particularly liver, heart, and lungs, characterized by mixed inflammatory cell infiltration, epithelial hyperplasia, and hypertrophy. Taken together, these findings suggest that IL-17E is a unique pleiotropic cytokine and may be an important mediator of inflammatory and immune responses.

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…Although much is now known regarding the biology of IL-17 in murine systems and there is compelling evidence for an important role of IL-17 in inflammatory/autoimmune conditions [52,53], attempts to overexpress IL-17A ubiquitously in mice have failed due to generalized overproduction being lethal to developing embryos [54], while overexpression of IL-17E leads to a generalized inflammatory syndrome [55]. In humans, there is also a considerable body of evidence suggesting an important role for IL-17 in the aetiopathogenesis of inflammatory and autoimmune diseases, as discussed below.…”

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

“…Accordingly, in vivo biologic activities of IL-25 are markedly different from those described for IL-17 and other IL-17 family cytokines (2-4, 8 -10). Remarkably, it has been shown that the enforced expression of IL-25 induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as eosinophilic airway inflammation, mucus production, and airway hyperreactivity (2)(3)(4)8).…”

“…I nterleukin-25 has recently been identified as the fifth member of the IL-17 cytokine family (IL-17E) by database searching (1)(2)(3)(4). The IL-17 family now consists of six family members, namely IL-17 (IL-17A), IL-17B, IL-17C, IL-17D, IL-25, and IL-17F (5-7).…”

“…It has recently been shown that TNFR-associated factor (TRAF) 3 family proteins play a critical role in a number of signaling pathways that activate NF-B (13)(14)(15)(16). TRAF family proteins contain a conserved TRAF-C domain that is essential for the interaction with their cognate receptors or cytoplasmic signaling proteins (13)(14)(15)(16).…”

Transcription of Interleukin-25 and Extracellular Release of the Protein Is Regulated by Allergen Proteases in Airway Epithelial CELLS

“…In contrast, IL-25 is exceptional in promoting eosinophilic inflammation and a type-2 immune response (7). This has been well demonstrated in mouse models: exogenous administration of IL-25 (8,9) or transgenic expression (10,11) induces Th2-type inflammation. IL-25 is increased in animal bronchial challenge models (12), and its inhibition reduces the associated Th2-type inflammation (13,14).…”