IL-17C regulates the innate immune function of epithelial cells in an autocrine manner

Abstract

Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the T(H)17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate-induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…9,[21][22][23][24] At present, the IL-17RA and IL-17RE heterodimer is considered the functional receptor for IL-17C. [25][26][27] IL-17RB has also been suggested to be a receptor for IL-17B; 28,29 however, evidence from genetic deficiency experiments is lacking for this receptor and ligand combination. Moreover, whether IL-17RA is required for the function of IL-17B is also unclear.…”

“…In contrast to the universal expression of IL-17RA, IL-17RE is mainly located on epithelial cells, keratinocytes or Th17 cells. [25][26][27] As described above, IL-17RA is a shared receptor of the IL-17 family of cytokines. Thus, IL-17RE is believed to act as a specific functional receptor for IL-17C.…”

“…165 On a molecular level, signals from the TLR and NOD2 pattern-recognition receptor mediate IL-17C induction in different types of epithelial cells. 25,26,166 Both the TLRMyd88-NF-κB and TLR-TRIF-NF-κB pathways are likely to be required for its induction. 26,167,168 The production of IL-17C is also controlled by inflammatory cytokines (that is, TNFα and IL-1β), which might be induced by PRR signaling during infection.…”

“…25,26,166 Both the TLRMyd88-NF-κB and TLR-TRIF-NF-κB pathways are likely to be required for its induction. 26,167,168 The production of IL-17C is also controlled by inflammatory cytokines (that is, TNFα and IL-1β), which might be induced by PRR signaling during infection. 25 IL-17 and IL-17F also induce IL-17C expression in intestinal epithelial cells, albeit at a reduced level.…”

“…DSS-induced colitis causes the overgrowth and translocation of E. coli species into the basolateral side of the intestinal epithelium where they trigger IL-17C production from these cells via TLR signaling. 26,165 Under colitis conditions, the monocolonization of E. coli in either germ-free mice or antibiotic-treated mice can sufficiently induce IL-17C expression in the colon. 165 IL-17C signaling maintains intestinal mucosal barrier integrity by inducing tight junction molecule or antibacterial gene expression in intestinal epithelial cells.…”