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Experimental autoimmune encephalomyelitis (EAE) has been widely employed as a model to study multiple sclerosis (MS). Interleukin-27 (IL-27) inhibits Th17 activity and breaks the normal activity of effector T cells which cause autoimmunity. Bee venom (BV) has been used as a form of medicine from the time of ancient Greece and China. BV and BV-derived active components might have potent therapeutic effects on refractory immunological and neurodegenerative diseases, such as MS. This study aimed to investigate the effect of Iranian honey bee venom on the progression of EAE in mice. Initially, EAE was induced in 12 female C57BL/6 mice through immunization with an emulsion of myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) in Complete Freund’s adjuvant (CFA), followed by administration of pertussis toxin (PTx) in phosphate buffer. Following the appearance of clinical signs, the mice were treated intraperitoneally with BV. Histopathological and immunological studies were investigated, and EAE was induced in animals within 9-14 days. Results revealed a significant reduction in IL-27 levels following EAE induction in mice. However, BV-treated mice showed a significant increase in IL-27, compared to controls. Histopathology results revealed that the number of inflammatory cells was reduced in the brain parenchyma following BV treatment. Based on the results obtained in the present study, BV may be a suitable candidate for the treatment of inflammatory diseases, such as MS. [ABSTRACT FROM AUTHOR]