류마티스관절염 치료의 새로운 표적으로써의 Phosphoinositide 3-kinase (PI3K) (Phosphoinositide 3-kinase (PI3K) as a New Therapeutic Target for Rheumatoid Arthritis)

서지정보

· 발행기관 : 대한류마티스학회
· 수록지 정보 : 대한류마티스학회지 / 20권 / 2호 / 74 ~ 82페이지
· 저자명 : 김해림

초록

Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5- bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5- triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110γ and p110δ of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110γ and p110δ is increased, and their up-regulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110γ and p110δ and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kγ and PI3Kδ. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.

영어초록

Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5- bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5- triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110γ and p110δ of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110γ and p110δ is increased, and their up-regulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110γ and p110δ and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kγ and PI3Kδ. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.

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