Inhibition of PI3Kδ improves systemic lupus in mice.
Systemic lupus erythematosus (SLE) is an autoimmune disease accompanying excessive inflammatory responses. Phosphoinositide 3-kinase p110δ (PI3Kδ) is reported to associate with autoimmune conditions. We here aimed to determine whether selective inhibition of PI3Kδ is effective in a lupus model of BXSB mice, using the selective PI3Kδ inhibitor IC87114, which was intraperitoneally administrated to BXSB mice aged from 14 to 22 weeks. We showed that IC87114 improved renal function by decreasing the levels of proteinuria and serum creatinine, ameliorating the pathologic changes of kidneys and IgG and C3 deposition. Serum anti-autoantibody to nuclear antigen, anti-dsDNA, IL-1β, and IL-17 were markedly reduced by IC87114 therapy. Hepatic damage was also inhibited by administration of IC87114. Expression of phosphorylated AKT (p-AKT) and monocyte chemoattractant protein-1 was inhibited and mouse survival improved. In sum, PI3Kδ activation may be a critical factor for escalating autoimmune renal and hepatic damage, and its inhibition may alleviate the autoimmune damage. Our study reveals that the selective blockade of PI3Kδ is effective for mouse SLE.
Department of Nephrology, General Hospital of Jinan Military Command, Jinan, 250031, China.
Yanxia
Y
Wang
Lei
L
Zhang
Ping
P
Wei
Huailiang
H
Zhang
Cuijie
C
Liu
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D018932:Chemokine CCL2 / Q000096:biosynthesis; D058534:Class I Phosphatidylinositol 3-Kinases; D003404:Creatinine / Q000097:blood; D020381:Interleukin-17 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D007668:Kidney / Q000473:pathology*; D007677:Kidney Function Tests; D008099:Liver / Q000473:pathology*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology*
D000974:Antibodies, Antinuclear; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C477872:IC 87114; C587672:IL1B protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D003404:Creatinine; D058534:Class I Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000225:Adenine