Sebaceous glands are holocrine glands that produce sebum, which primarily contains lipids that help maintain the barrier function of the skin. Dysregulated lipid production contributes to the progression of some diseases characterized by dry skin, including atopic dermatitis. Although the lipid production of sebaceous glands has been well studied, few studies have assessed their role in skin immune responses. We found that sebaceous glands and sebocytes expressed interleukin (IL)-4 receptor and produced high levels of Th2-associated inflammatory mediators following IL-4 treatment, suggesting immunomodulatory effects. Galectin-12 is a lipogenic factor expressed in sebocytes that affects their differentiation and proliferation. Using galectin-12-knockdown sebocytes, we demonstrated that galectin-12 regulated immune response in cells exposed to IL-4 and promoted CCL26 expression by upregulating PPARγ. Moreover, galectin-12 suppresses the expression of endoplasmic reticulum (ER) stress-response molecules and CCL26 upregulation by IL-4 was reversed following sebocyte treatment with inducers of ER stress, suggesting that galectin-12 controls IL-4 signaling by suppressing ER stress. Using galectin-12-knockout mice, we demonstrated that galectin-12 positively regulated the IL-4-induced enlargement of sebaceous glands and development of an atopic dermatitis-like phenotype. Thus, galectin-12 regulates the skin immune response through promoting PPARγ expression and suppressing ER stress in sebaceous glands.