Fatty acid transport protein 1 enhances the macrophage inflammatory response by coupling with ceramide and c-Jun N-terminal kinase signaling

Kazuhiro Nishiyama, Takashi Fujita, Yasuyuki Fujimoto, Hidemitsu Nakajima, Tadayoshi Takeuchi, Yasu Taka Azuma

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Macrophages are important cells that need to be controlled at the site of inflammation. Several factors are involved in chronic inflammation and its timely resolution. Free fatty acids drive the inflammatory response in macrophages and contribute to the vicious cycle of the inflammatory response. However, the identity of the uptake pathways of fatty acids is not fully clear in macrophages and how the inflammatory responses are regulated by the uptake of fatty acids remain poorly understood. We investigated the relationship between fatty acid transport protein (FATP) and the inflammatory response signaling pathway in macrophages as the first report. The FATP family has composed six isoforms, FATP1-6. We found that FATP1 is the most highly expressed isoform in macrophages. Forced expression of FATP1 enhanced production of inflammatory cytokines, such as TNFα and IL-6 concomitant with the increased uptake of fatty acids, increased level of ceramide, and increased phosphorylation of c-Jun N-terminal kinase (JNK). The enhancement by FATP1 was abolished by treatment with a JNK inhibitor, NF-κB inhibitor, or ceramide synthesis inhibitor. siRNA-mediated knockdown of FATP1 strongly inhibited the production of TNFα and IL-6. Similarly, an inhibitor of FATP1 inhibited the production of TNFα and IL-6. Finally, an inhibitor of FATP1 attenuated the production of inflammatory cytokines in bronchoalveolar lavage fluid in an LPS-induced acute lung injury in vivo mouse model. In summary, we propose that FATP1 is an important regulator of inflammatory response signaling in macrophages. Our findings suggest that ceramide-JNK signaling is important to terminate or sustain inflammation.

Original languageEnglish
Pages (from-to)205-215
Number of pages11
JournalInternational Immunopharmacology
Volume55
DOIs
Publication statusPublished - Feb 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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