A novel aminosaccharide compound blocks immune responses by Toll-like receptors and nucleotide-binding domain, leucine-rich repeat proteins.
Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR- or NLR-induced activation of p38 and JNK, phosphorylation/degradation of IκB, and subsequent nuclear translocation of NF-κB subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Kyoung-Hee
KH
Lee
Yuen-Joyce
YJ
Liu
Amlan
A
Biswas
Chikako
C
Ogawa
Koichi S
KS
Kobayashi
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000606:Amino Sugars / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001710:Biotin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D000090263:Leucine-Rich Repeat Proteins; D048670:MAP Kinase Kinase 4 / Q000276:immunology; D051379:Mice; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D000606:Amino Sugars; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C557317:DFK 1012; D018836:Inflammation Mediators; D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; C498144:Rela protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D001710:Biotin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000117:Acetylglucosamine