The type III interferon family (IFN-III), including IFN-λ3 (IL-28B), has antiviral, anti-tumor, and immunomodulatory activities. Although IL-28B anti-tumor effect has been extensively explored, its underlying anti-tumor mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. We found that IL-28B significantly inhibited colon cancer growth in a murine MC38 tumor cell engraftment model. Interestingly, IL-28B did not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro. IL-28B treatment exerted indirect anti-tumor activity by downregulating M2 macrophages in the tumor microenvironment. Furthermore, IL-28B inhibited M2 macrophage polarization in vitro. It also halted M2 macrophage differentiation predominantly via inhibition of the STAT3 and JNK signaling pathways. Our findings revealed that IL-28B inhibited M2 macrophages in the tumor microenvironment to delay colon cancer progression. Our study provides new evidence of IL-28B anti-tumor and immunomodulatory activities.

Background and Purpose: Psoriasis is an immune-associated disease, however, the pathogenesis of psoriasis remains unclear. We investigated the mechanism of IL-35 in psoriasis treatment. Experimental Approach: PASI and Baker scores were used to evaluate the Imiquimod-induced psoriasis mouse model. Flow cytometry is used to detect changes in immune cells and to select target cells. The changes of inflammatory factors were detected by ELISA. Adoptive transfused was used to demonstrate the effect of the corresponding cells. Key Results: IL-35 expression in patients with psoriasis was significantly increased. The number of myeloid-derived suppressor cells (MDSCs) in patients was also significantly increased. Similar results were obtained in mice with imiquimod (IMQ)-induced psoriasis. IL-35 had potent immunosuppressive effects on psoriasis model mouse, leading to a decrease in the total number of MDSCs and its subtypes in the spleen and psoriatic skin lesions. The level of inducible nitric oxide synthase (iNOS) secreted by MDSCs also decreased significantly; however, there was no difference in the level of IL-10 in MDSCs. Adoptive transfer of MDSCs from IMQ-challenged mice weakened the effect of IL-35. When MDSCs were isolated from iNOS knockout mice that were established with IMQ and transfected into IMQ-induced WT mice, there was no significant difference in psoriasis area and severity index scores between IL-35 + iNOS-/–MDSC and IL-35 treatment groups. Conclusions and Implications: IL-35 plays an important immunosuppressive role in psoriasis by inhibiting the counts of MDSCs expressing iNOS. This study may serve as a new therapeutic strategy for patients with chronic psoriasis or other cutaneous inflammatory diseases.

Extracellular adenosine triphosphate (eATP) mediates pro-inflammatory responses by recruiting and activating inflammatory cells. eATP is hydrolyzed by CD39 to adenosine monophosphate (AMP), which is converted to the immunosuppressive nucleoside adenosine (ADO) by CD73. CD39 is the rate-limiting enzyme in this cascade and can be viewed as an immunological switch that shifts ATP-driven pro-inflammatory immune cell activity to an anti-inflammatory state mediated by ADO. CD39 is expressed by a broad range of immune cells and can be influenced by genetic and environmental factors. Accumulating evidence suggests that CD39 is involved in several pathophysiological events, such as inflammatory bowel diseases, sepsis, ischemia-reperfusion injury, allergic diseases, systemic lupus erythematosus, diabetes, and cancer. Here, we focus on the current understanding of CD39 in immunity, and presents a comprehensive picture of the multiple roles of CD39 in a variety of disorders.