Objective To investigate the regulatory effects of activated endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) on the immune behavior of the stressed muscle fibers in inflammatory environments induced by interferon-γ(IFN-γ).   Methods The myogenic precursor cells (MPCs) of C57 BL/6 mice cultured in vitro were differentiated into multinucleated myogenic tubes by horse serum and then to set up: 1. Control group; 2. IFN-γ group; 3. Tunicamycin group; 4. Thapsigargin group; 5. IFN-γ and 4-phenylbutyrate(4-PBA) combined treatment group; 6. IFN-γ, TG and 4-PBA combined treatment group; 7. IFN-γ and 4μ8c combined treatment group; 8. IFN-γ, TG and 4μ8c combined treatment group; 9. IFN-γ and GSK2606414 combined treatment group; 10. IFN-γ, TG and GSK2606414 combined treatment group. The level of myokines gene was detected by Real-time PCR. The expression of UPR key molecules including eukaryotic intiatio factor 2α(eIF2α), inositol requrring enzyme 1α(IRE1α) and activating transcription factor 6(ATF6) in muscle fibers was observed by immunofluorescence. Western blotting was used to detect immune molecules related to muscle cells, myokines and key molecules of UPR. Luminex analyzed the levels of pro-inflammatory myokines in muscle fibers.   Results The expression of H-2Kb, H2-Ea, Toll like receptor 3(TLR3), p-eIF2α and p-IRE1α were up-regulated in IFN-γ induced inflammatory environment. The expression of H-2Kb, H2-Ea, TLR3 and myokines in the group with UPR inhibitor 4-PBA was down-regulated compared with IFN-γ group, and the expression of these molecules in the group with IRE1α specific inhibitor 4μ8c was down-regulated compared with the IFN-γ group. The addition of protein kinase R-like endoplasmic eticulum(PERK) specific inhibitor GSK2606414 showed no significant change.  Conclusion In IFN-γ induced inflammatory environment, the UPR-IRE1α pathway activates and inhibits the synthesis of muscle fiber immune-related molecules, which further inhibits the muscle fiber mediated immune response and facilitates muscle regeneration.