Abstract Backgrounds and purpose: Anti-TNF therapy have gained great success in autoimmune disease. However, insufficient efficacy and safety of high dosage anti-TNF agents are exposed in amounts of clinical cases. Aiming at improving therapeutic of anti-TNF therapy, an anti-TNF nanobody V19 and combination therapy with PGE2 was introduced. Experimental Approach: DSS-induced colitis mice was used for evaluating therapeutic effect of V19 and combination therapy. Variation of Treg/Th17 balance was raised as the criterion for comparing therapeutic with combination therapy and mono-therapy. Key Results: V19 expressed by Escherichia. coil showed therapeutic effect on DSS-induced colitis mice by inducing the increase of treg via up-regulating tm-TNF-α and TNFR2 in peripheral blood. However, cell apoptosis (treg, Dendritic Cells and CD8 T cells) was induced in peripheral blood under high dose of V19 accompanied with up-regulated tm-TNF-α. Besides, Th17 cells in colons from DSS-induced mice were induced by V19 accompanied with up-regulation of IL-6. Combination therapy presented better therapeutic effect than mono-therapy. After combination therapy, Th17 cells were significantly decreased in colons and vitro assay demonstrated that PGE2 reduced Th17 cells by down-regulating IL-6 in colons via EP4. Although PGE2 showed no influence on cell apoptosis and can not induce treg generation, it enhanced the ability of V19 in inducing treg by up-regulating TNFR2 via EP4 in peripheral blood. Conclusion: This combination therapy presents good clinical significance that combination of PGE2 can expand drug delivery window and enhanced therapeutic effect during the anti-TNF clinical treatment.