| Rheumatoid arthritis(RA) is a chronic autoimmune disease, which is characterized by synovium inflammation, hyperplasia and pannus formation, leading to bone and cartilage destruction. Many studies demonstrate that cytokines play a pivotal role in the pathogenesis of RA although the exact causes are still unclear. Antigen-activated CD4+T cells stimulate monocytes and macrophages to produce proinflammtory cytokines including TNF-α,IL-1β,IL-6 and matrix metalloproteinase (MMP). Fibroblast-like synoviocytes (FLS) respond to several cytokines such as monocyte and macrophage-derived products, platelet-derived growth factor(PDGF) and exhibit characteristics of inflammatory cells. FLS secrete MMPs including MMP2 and MMP9, leading to bone and cartilage degradation. They are also involved in the infiltration and activation of other immune cells in the synovium by secreting IL-6 or expressing intercellular adhesion molecular-1(ICAM-1) and vascular cell adhesion molecular-1(VCAM-1). Therefore, FLS are crucial effector in joint inflammation and destruction. Regulating of cytokine secretion of FLS may be important in the pathogenesis and progression of RA.It has been proved that several neuropeptides/hormones including growth hormone, somatostatin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide(PACAP), cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), neuropeptide Y and neurotensin had anti-shock and anti-inflammation effects, which participated in the central nervous system (CNS)- endocrine system- immune system network regulation. For recent years, a series of studies in our laboratory has been focused on the effect ofcholecystokinin octapeptide (CCK-8) against endotoxin shock (ES) and inflammation. Pretreating ES rats with CCK-8 led to lower mortality rate, amelioration of interstitial edema and inflammatory infiltration in lung, spleen and kidney, reduction in pulmonary arterial hypertension (PAH), and inhibition of TNF-α,IL-1β,IL-6 produced by lung and spleen; In addition, CCK-8 can also inhibit TNF-α production, transcription and activation of NF-κB induced by LPS in pulmonary interstitial macrophages in vitro, downregulated the expression of LPS receptor CD14. Recently, the theraputic effects of neuro-intestinal peptide VIP and PACAP in collagen-induced arthritis, an animal model of human RA, was very noticeable. It seems that VIP and PACAP have the ability to decrease incidence and severity of CIA, regulate Th1/Th2 balance, downregulate inflammatory response, inhibit MMP expression an activity. In vitro, VIP markedly inhibited IL-6 and IL-8 production by RA FLS.These results strongly suggested neuro-intestinal peptides may be useful in therapy of RA. Recent study showed that CCK-8 regulated the carrageenan-induced arthritis through controlling nerve growth factor (NGF), but had no direct anti-inflammatory effect in this autoimmune arthritis model. Untill now, there is no report about the regulation effect of CCK-8 on cytokine production of synoviocytes.The increased cytokine productions, expression of adhesion moleculars and synthesis of destructive enzymes play a pivotal role in the perpetuation of RA. It is well recognized that NF-κB is a major regulator in expression of proinflammatory cytokine genes. Also, NF-κB is essential for cytokine production such as TNF-α, IL-1β and the expression of COX-2 in RA. Activation of NF-κB led to the expression of adhesion molecular E selectin, ICAM-1 and VCAM-1, whereas inhibition of NF-κB reduced the adhesion and migration of leucocytes. NF-κB activation also increased the expression of MMP and severity of joint inflammation in CIA. In addition, inhibition of NF-κB contributed to synoviocyte proliferation. These results indicated that NF-κB involved inpathogenesis of RA. In resting cells, NF-κB is retained in the cytoplasm through an interaction with inhibitory protein known as IκB. Upon cell activation by extracellular stimuli, IκB is phosphorylated, ubiquitinated, and degrada...
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