Fibrosis is a leading cause of morbidity and mortality worldwide. In the USA, 45% of all deaths can be attributed to fibrotic disorders (Wynn, 2004). In the liver, fibrosis and its end stage, cirrhosis, is the final common pathway of chronic liver diseases irrespective of etiology (Iredale, 2007). Liver cirrhosis represents not only increased scarring and fibrosis, but also distortion of the liver architecture in association with nodule formation and altered blood flow (Friedman, 2008). Patients with liver cirrhosis are facing tremendous risks of hepatic failure and hepatocellular carcinoma (Friedman, 2008). So far, there is no gold-standard treatment for liver fibrosis and cirrhosis.

Advancement of liver fibrosis is a dynamic process characterized by accumulation exceeding degradation of extracellular matrix (ECM). Over the last two decades, sinusoidal resident hepatic stellate cells (HSC) have been commonly recognized as the major source of ECM. In most chronic liver diseases, HSC activation and transdifferentiation into myofibroblasts (MFBs) are key events in liver fibrogenesis (Friedman, 2008). The initiation phase of HSC activation is due to paracrine stimuli from injured neighboring cells, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, platelets, and infiltrating inflammatory cells. These damaged cells secret a number of cytokines to activate HSC. One important cytokine among them is transforming growth factor (TGF)-β. Activated HSC perpetuate their own activation by several autocrine loops, including the secretion of TGF-β and upregulation of its receptors. Furthermore, overexpression of TGF-β promotes HSC survival in damaged liver (Bataller and Brenner, 2005; Mann and Marra, 2010).

As the most important pro-fibrotic mediator in liver fibrosis (Gressner et al., 2002; Friedman, 2008), the role of TGF-β has been intensively studied in a large amount of in vitro and animal models. However, in patients with chronic liver diseases, the effects of TGF-β in liver fibrogenesis are etiology dependent (Weng et al., 2009). For example, TGF-β and its downstream signaling protein, phospho-Smad2, display high positive correlation with fibrosis degree in patients with chronic HBV infection, alcoholic steatohepatitis (ASH), and non-alcoholic steatohepatitis (NASH), but not in those with chronic HCV infection. In patients infected with Schistosoma mansoni or S. japonicum, TGF-β demonstrates negative correlation with fibrosis stages (Weng et al., 2009; Table 1).

Besides TGF-β, Interleukin (IL)-13 is recognized as another critical pro-fibrotic cytokine in various organs, including liver. It has been identified as the dominant effector cytokine of Schistosomiasis associated liver fibrogenesis (Wynn, 2003, 2004, 2008). Over the last decade, the potential roles of IL-13 in non-Schistosomiasis associated liver fibrogenesis were reported (Weng et al., 2009; Jin et al., 2011). In this review, we aim to provide up-to-date information on the role of IL-13 and its downstream signaling in fibrogenesis, especially in the liver.

Besides Schistosomiasis, Th2 type cytokines are dominant in a series of fibrotic diseases, including interstitial lung disease, systemic sclerosis, rheumatoid arthritis (RA), and Ulcerative colitis (UC; Wynn, 2003, 2004, 2008).

In idiopathic interstitial pneumonia (IIP), IL-13 expression in tissue and in bronchoalveolar lavage (BAL) fluid is elevated in the most common subgroup, idiopathic pulmonary fibrosis (IPF). IPF is considered a Th2 type disease with inflammatory infiltrates prevalent. IL-13 levels were higher in IPF than in the non-specific interstitial pneumonia (NSIP), the second most common IIP without inflammatory infiltrates, but with less fibrosis and better prognosis (Park et al., 2009). In progressed stages of sarcoidosis, IL-13 expression is highly elevated in BAL and in peripheral blood mononuclear cells, compared to lower disease grades and healthy controls (Hauber et al., 2003), suggesting the elevated expression of IL-13 might be a potential therapeutic avenue in this disease. The connection of IL-13 to lung fibrosis was further strengthened in animal models. In a mouse model of chronic asthma, IL-13 proved paramount in airway remodeling, eosinophile accumulation and fibrosis (Kumar et al., 2002). Further, inhibition of IL-13 signaling via blocking antibodies underlined the importance of IL-13 in interstitial lung disease, either in animals which were challenged with Aspergillus fumigatus Conidiae (Blease et al., 2001), or animals with bleomycin-induced lung fibrosis (Belperio et al., 2002). In transgenic mice, overexpressing IL-13 in the lungs resulted in fibrosis (Zhu et al., 1999).

Further studies showed that IL-13 stimulates airway remodeling via induction of specific MMP’s (Lanone et al., 2002), and IL-13 is capable of acting directly on airway fibroblasts and supporting their proliferation (Belperio et al., 2002) via induction of PDGF-alpha (Ingram et al., 2004).

Elevated IL-13 levels have also been reported in systemic sclerosis, in RA, and other rheumatic diseases (Spadaro et al., 2002). The first study connecting IL-13 to systemic sclerosis (SSc) was published in 1997. The authors showed significantly elevated IL-13 levels in the sera of patients with limited cutaneous SSc (lSSc) and diffuse cutaneous SSc (dSSc) compared to healthy individuals (Hasegawa et al., 1997). Further, IL-13 levels were found to correlate to more aggressive stages of disease (Riccieri et al., 2003). In an animal model of systemic sclerosis, in which Bleomycin is administered subcutaneously, similar observations have been achieved (Matsushita et al., 2004). Consequently, Wynn et al. proved that IL-13 is responsible for the fibrosis in bleomycin-induced SSc, and its expression is regulated by the transcription factor T-bet (Aliprantis et al., 2007).

Rheumatoid arthritis, a disease in which joint inflammation and fibrosis occurs, has long been regarded as a Th1 cell induced disease and lack of Th2 responses (Toh and Miossec, 2007). Recent studies demonstrate that Th17 cells play important roles in RA (Toh and Miossec, 2007). However, besides Th1 and Th17 cells secreted cytokines, increased IL-13 levels in patients’ sera and synovial fluids were also detected (Isomaki et al., 1996; Spadaro et al., 2002). Further, Treatment with anti-TNF alpha antibody decreases IL-13 levels (Spadaro et al., 2002; Tokayer et al., 2002). Another study also showed elevated IL-13 levels in Still’s disease, an adult form of juvenile RA (Saiki et al., 2004). However, animal models which connect Il-13 to extensive scarring in RA are still missing to date.

Ulcerative colitis is also considered a TH2 type disease, with recurring episodes of colonic inflammation, and in the terminal stadium widespread fibrosis occurs. It is hypothesized that IL-13 derived from mononuclear cells, is involved in the pathogenic changes (Heller et al., 2005). However, in an animal model of colitis, IL-13 proved to be beneficial in preventing inflammatory changes (Wilson et al., 2011), whereas another study points out its proinflammatory role in UC (Kawashima et al., 2011).

IL-13 signals to cells by binding to a complex receptor system comprised of IL-4Rα and two IL-13 binding proteins, IL-13Rα1 and IL-13Rα2 (Zhang et al., 1997). IL-13 Rα1 is expressed in healthy tissue and binds IL-13 with low affinity by itself, but when paired with IL-4α, it binds IL-13 with high affinity and forms a functional IL-13 receptor that signals and results in activation of JAK/Stat6 pathway (Hershey, 2003; Figure 1). IL-13Rα2, on the other hand, is only marginally expressed in normal tissues, but over-expressed in several abnormal conditions, including in cancer cells and during fibrosis (Jakubzick et al., 2002, 2004; Joshi et al., 2006). In contrast to its interaction with the IL-13Rα1, IL-13 shows higher affinity binding to IL-13Rα2 which has a short cytoplasmic tail and thus is generally considered a decoy receptor in murine system as described above (Chiaramonte et al., 2003; Mentink-Kane et al., 2004; Wynn et al., 2004a). However, Fichtner-Feigl et al. recently reported that IL-13 signals through IL-13Rα2 to induce production of TGF-β1 in murine macrophage cell line. Silencing IL-13Rα2 markedly reduces TGF-β1 and ameliorates bleomycin-induced mouse lung fibrosis (Fichtner-Feigl et al., 2006). Furthermore, IL-13 signals through IL-13Rα2 in HSC leading to TGF-β1 production and liver fibrosis in vitro and in a NASH model (Shimamura et al., 2008). These findings nevertheless provide us new insights for understanding IL-13 function and signaling in different fibrotic diseases. More advanced acknowledge with IL-13Rα2 is thus eagerly awaited.

Given that both TGF-β1 and IL-13 are critical for organ fibrosis, synergic signaling crosstalk during fibrogenesis between these two major pro-fibrotic cytokines is always a hot topic. IL-13 cooperates with TGF-β1 to induce fibrosis in some settings (Lee et al., 2001; Lanone et al., 2002; Fichtner-Feigl et al., 2006). For example, IL-13 is known as a potent inducer of matrix metalloproteinases-9 and cathepsin-based proteolytic pathways which stimulate cleavage of latency-associated peptide thus activate TGF-β (Lee et al., 2001; Lanone et al., 2002). However, the mechanism of IL-13 induced fibrogenesis is far more complicated than expected. In the context of schistosoma infected mice, IL-13 induced liver fibrosis is independent of TGF-β (Kaviratne et al., 2004). A more recent work studying CTGF induction in primary HSC further supported a TGF-β independent mechanism involved in IL-13 induced liver fibrogenesis (Liu et al., 2011). IL-13 was found to induce CTGF in a TGF-β independent manner in quiescent HSC, while this process still requires activation of Smad proteins and participation of TGF-β type I receptors. Erk–MAPK signaling pathway was found at least partially to mediate the TGF-β independent Smads activation involved in IL-13 stimulated CTGF production (Liu et al., 2011; Figure 1). These findings suggested that IL-13 mediated fibrosis may be not strictly dependent on the downstream TGF-β actions. Besides through regulating the production and activation of TGF-β, IL-13 can also utilize other mechanisms to drive fibrogenesis.

Another controversial issue involved in IL-13 mediated fibrogenesis is the participation of Stat6. Signaling through IL-4Rα/IL-13Rα1 supports Stat6 activation for both IL-4 and IL-13, which is consistent with the fact that IL-13 shares many functional properties with IL-4. Stat6 activation upon receptor engagement is suggested due to the recruitment of Stat6 to the IL-4Rα chain (Kelly-Welch et al., 2003). A number of studies have demonstrated that the IL-13, IL-4Rα, and Stat6 pathway is critical for development of fibrosis (Fallon et al., 2001; Lee et al., 2001; Chiaramonte et al., 2003). On the other hand, several studies argued that IL-13-regulated response, including lung and liver fibrosis, could develop in the absence of Stat6 (Blease et al., 2002; Fritz et al., 2011; Liu et al., 2011). A study based on liver tissue from patients with different chronic liver diseases revealed that only 5 of 120 IL-13 positive liver tissue specimens exhibited positive p-Stat6 staining (Weng et al., 2009), indicating that a Stat6 independent mechanism is implicated in IL-13 associated liver fibrosis.

It has been confirmed that IL-13 is a critical pro-fibrotic factor in liver fibrosis associated with Schistosoma infection. In cultured HSC, IL-13 directly up-regulates expression of collagens and other pro-fibrotic genes. Recently, the potential role of IL-13 in non-Schistosoma induced liver fibrogenesis has been uncovered. The IL-13 receptors, IL-13Rα1 and IL-13Rα2, play differently in IL-13 signaling pathway. IL-13Rα2 serves as a decoy receptor in Schistosomiasis, but transmits signaling to activate TGF-β1 promoter in NASH. What is the function of IL-13Rα2 in other IL-13 related chronic liver diseases? Is it possible to use sIL-13Rα2-Fc as a successful drug to treat liver fibrosis in Schistosomiasis patients? What kind of role is Stat6 playing in different diseases settings? These are some eager questions waiting to be explored in the near future.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.