Juniperus rigida Sieb. extract inhibits inflammatory responses via attenuation of TRIF-dependent signaling and inflammasome activation.
BACKGROUND
Juniperus rigida Sieb. (J. rigida) is used for medicinal purposes in Asian countries to treat inflammation-related disorders, such as neuralgia, dropsy, and gout.


OBJECTIVE
The anti-inflammatory effects of J. rigida extract (JR) and its underlying mechanisms were explored both in in vitro cell lines and in vivo metabolic disease models.


METHODS
Lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages were used to study the changes in inflammatory responses in vitro. Bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of JR on inflammasome activation. The murine model for monosodium urate (MSU)-induced peritonitis and high-fat diet (HFD)-induced type 2 diabetes were employed to study the effect of JR on in vivo efficacy.


RESULTS
JR suppressed the MSU-induced in vivo inflammatory response by attenuation of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). In the in vitro study, JR suppressed IL-1β secretion via regulation of apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, leading to the inhibition of inflammasome activation. JR also inhibited the LPS-stimulated release of proinflammatory mediators, such as nitric oxide (NO), TNF-α, and IL-6 in RAW264.7 cells. The inhibitory effects of JR were mediated through the regulation of the TRIF-dependent signaling pathway from JAK1/STAT1 phosphorylation. Furthermore, JR showed inhibitory effects on HFD-induced type 2 diabetes in a mouse model through the regulation of blood glucose and serum IL-1β.


CONCLUSIONS
Our results indicate that JR attenuates both LPS-stimulated and danger-signal-induced inflammatory responses in macrophages via regulation of the key inflammatory mechanisms, providing scientific support for its traditional use in the treatment of various inflammation-related metabolic disorders.
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Ji-Won
JW
Han
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Do-Wan
DW
Shim
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Woo-Young
WY
Shin
Department of Food Science and Engineering, Seowon University, Cheongju, South Korea.
Myong-Ki
MK
Kim
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Eun-Jeong
EJ
Shim
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Xiao
X
Sun
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Sushruta
S
Koppula
Division of Biological Science and Technology, Institute of Biomaterials, Yonsei University, Wonju, South Korea.
Tack-Joong
TJ
Kim
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea.
Tae-Bong
TB
Kang
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, Konkuk University, Chungju, South Korea. Electronic address: kwangho@kku.ac.kr.
Kwang-Ho
KH
Lee
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D018653:Juniperus / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D000067996:RAW 264.7 Cells; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014527:Uric Acid
D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D007004:Hypoglycemic Agents; D058847:Inflammasomes; D018836:Inflammation Mediators; D053613:Janus Kinase 1; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010936:Plant Extracts; D050794:STAT1 Transcription Factor; D014527:Uric Acid; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; C494080:Stat1 protein, mouse; C476286:Ticam1 protein, mouse; C507905:Jak1 protein, mouse
ASC; IL-1β; Inflammasome; Juniperus rigida; TRIF; Type-II diabetes