Leukotriene B₄ amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

Serezani, C.H., et al. 2011. J. Clin. Invest. 121: 671-682

Speaker: Yu-Ting Liao (廖郁婷)                                    Time: 14:10~15:00, Mar. 9, 2011

Commentator: Dr. Chi-Chang Shieh (謝奇璋老師)     Place: Room 601

Abstract:

Leukotriene B₄ (LTB₄) serves as a mediator in 5-lipoxygenase-mediated (5-LO-mediated) biosynthesis and has been implied its function of antimicrobial defense. Several studies suggested that 5-LO metabolites involved in LPS-induced response. However, the role of LTB₄ in regulating TLR signaling and cytokine responses is still unknown. First, the authors found that production of NF-κB-dependent cytokines enhanced by MyD88-dependent agonists depend on 5-LO metabolites in vitro and in vivo. The DNA binding activity and LPS-induced translocation of NF-κB were attenuated in 5-LO^-/- and BLT1^-/- macrophages. Exogeous LTB₄ restored MyD88 expression in 5-LO^-/- ,but not in BLT1^-/- macrophages. The activation of MyD88 transcription factor STAT1 increased by LTB₄ which depended on JAK2 phosphorylation and Gαi signaling. Moreover, LTB₄/BLT1/Gαisignaling restrained SOCS1 by enhancing its mRNA degradation. By using siRNA to knockdown SOCS1, MyD88expression and LPS-induced secretion of proinflammatory molecules were recovered. Collectively, the results showed that LTB₄/BLT1/Gαi axis reduced SOCS1 to inhibit JAK2/STAT1-mediated MyD88expression and further influence the production of NF-κB-dependent cytokines in TLR-induced responses.

References:

1.      Peters-Golden, M., et al. 2007. Leukotrienes. N. Engl. J. Med. 357:1841-1854.

2.      Peters-Golden, M., et al. 2005. Leukotrienes: Underappreciated Mediators of Innate Immune Responses. J. Immunol. 174:589-594.

3.      Yasukawa, H., et al. 2000. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18:143-64.