Regulation Of Cytokines In Macrophage By Kruppel-like Factor10

Macrophages are considered to be important effector cells that play critical roles in innate immune system and also important antigen presenting cells which contribute to adaptive immunity. Macrophages are now classified as M1(classic activated macrophages) and M2(alternative activated macrophages).Bone marrow derived macrophage (BMM) can be respectively treated with GM-CSF or M-CSF and induced to GM-BMM or M-BMM which resembles a M1or M2profile. GM-BMMs make large amounts of proinflammatory cytokines and mediate resistance to pathogens while M-BMMs produce anti-inflammatory cytokines that contribute to tissue repairing and remodeling. M-BMMs stimulated with LPS are in an anti-inflammatory state with an IL-12lowIL-10high phenotype, but how this is regulated still remains unclear.K1f10belongs to the family of Kruppel-like transcription factors and is initially described as transforming growth factor-beta (TGF-beta) inducible early gene1(TIEG1). Here we report our studies that K1f10can regulate the production of IL-12p40, a common subunit shared by IL-12p70and IL-23in M-BMMs. We found IL-12p40was dramatically up-regulated in lipopolysaccharide (LPS) stimulated M-BMMs derived from K1f10deficient mouse. Phenotype analysis of cell surface markers revealed that there were no significant differences in M-BMMs between K1f10deficient mouse and wildtype mouse, which indicated that K1f10may not be involved in the differentiation of macrophages. Klfll, another member of KLF family which share high conserved consensus sequences with K1f10, could also participate in the regulation of IL-12p40.Mechanistic studies demonstrated that K1f10can bind to the CACCC element of the IL-12p40promoter and inhibit its transcription. The expression of CCAAT/enhancer-binding protein-a(C/EBP-a) and interferon regulatory factor8(IRF8) were also affected, which may be involved in the regulation of IL-12p40. In addition, the regulation of IL-12p40by K1f10was also found in a LPS mediated murine endotoxin shock model, which indicated a critical role of K1f10in inflammation induced by bacterial infections. Taken together, we identified K1f10as a transcription factor in M-BMMs that were able to regulate the expression of IL-12p40. Furthermore, it may play an important role in host innate and adaptive immune responses.