The classical IFN family cytokines, such as types I and II IFNs, are known to play an important role in both innate and adaptive immune responses during viral infection and autoimmune inflammation. Type III IFNs, or IFN-λs, are a newly described member of the IFN family, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B). Each member of type III IFNs signals through the heterodimeric receptor complex, including the IFN-λR (IL-28Rα) chain and IL-10 receptor type 2 (IL-10R2) chain [1, 2]. IL-28Rα expression is cell-specific, whereas IL-10R2 is broadly expressed in most cell types, such as type I IFN receptors . Type III IFNs bind to their receptors and activate the Janus kinase/signal transducers and activators of transcription (JAK-STAT), mitogen-activated protein kinase and Akt signaling pathways to induce antiviral, antiproliferative, antitumor and immune responses [3–5]. Although the antiviral activity has been studied extensively during the past decade, the immunoregulatory role of type III IFNs in immune cells is still poorly understood.
The evidence for an immunoregulatory role of IL-29 is derived mostly from in vitro studies. For example, IL-29 inhibits the release of IL-13 in T cells [6, 7]; increases the production of IL-6, IL-8 and IL-10 in macrophages ; and induces the secretion of IL-6 and TNF from CD14+ T cells  as well as IL-4 and IL-13 from mast cells . Investigators in a recent study reported that IL-29 induces the secretion of chemokines IFN-γ-inducible protein 10, monokine induced by IFN-γ and IL-8 in peripheral blood mononuclear cells (PBMCs) [11, 12] in patients with systemic lupus erythematosus (SLE), implying its involvement in SLE pathogenesis. Significantly, our recent study was the first showing that IL-29 was highly expressed in PBMCs, serum, synovial fluid and synovium in rheumatoid arthritis (RA) patients . However, little is known about what triggers the expression of IL-29 and how elevated IL-29 levels drive synovial inflammation during RA development.
It has recently been postulated that the interaction of genetic and environmental factors contributes to RA pathogenesis. For instance, Toll-like receptors (TLRs) may recognize cytomegalovirus [14, 15] and Epstein-Barr virus  and trigger autoimmunity in the host. TLRs are phylogenetically conserved molecules that recognize pathogen-associated molecular patterns and eliminate invading pathogens by activation of immune responses. In RA, several TLRs, including TLR2, TLR3, TLR4 and TLR7, are highly expressed in the synovial tissues , and the ligands of TLRs induce the expression of cytokines (IL-1β, IL-6 and IFN-α), chemokines (IL-8) and matrix metalloproteinases on synovial fibroblasts (FLSs) [18–21], which contributes to RA synovial inflammation. Interestingly, proinflammatory cytokines such as IL-1β itself further upregulate TLR expression on FLSs [22, 23], suggesting autoamplification of inflammation in RA-FLS through interaction of TLRs and cytokines.
This notion is further supported by the evidence that IFNs are able to modulate TLR-mediated cytokine production in immune cells. It has been shown that IFN-α enhances the expression of TLR3 and TLR7, leading to increased production of IL-6 and TNF-α in RA-FLS . In addition, TLR4- and TLR8-induced p40 subunit of IL-12 (IL-12p40) production is increased by IL-29 in human monocyte-derived macrophage . Despite this evidence, whether IL-29 is also involved in TLR-induced proinflammatory cytokine production in RA-FLS has not been reported. Considering that both IL-29 and TLRs could elevate mRNA levels of IL-6 and IL-8 in RA-FLS, we examined the effect of IL-29 on TLR-mediated IL-6 and IL-8 production contributing to RA inflammation.
In the present study, we show for the first time that TLR2, TLR3 and TLR4 engagement on RA-FLS induces endogenous IL-29, which further enhances IL-6 and IL-8 expression by upregulation of TLR2, TLR3 and TLR4 expression. Our findings demonstrate that, in addition to its potent antiviral activity, IL-29 plays an important role in modulating cytokine production in RA-FLS, which may enhance immune responses to the pathogens contributing to RA inflammation.