IL-4 and IL-12 regulate proteoglycan-induced arthritis through stat-dependent mechanisms
IL-4 and IL-12 regulate proteoglycan-induced arthritis through stat-dependent mechanisms
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DOI：
10.4049/jimmunol.169.6.3345
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发表时间：
2002-09-15
影响因子：
4.4
通讯作者：
Zhang, J
中科院分区：
文献类型：
--
作者：
Finnegan, A;Grusby, MJ;Zhang, J
IL-4是一种公认的巨噬细胞活化调节剂，被认为是一种抗炎细胞因子；然而，在某些情况下，IL-4可能起到促炎细胞因子的作用。我们之前已经证明，IL-4治疗患有蛋白多糖诱导关节炎（PGIA）的小鼠可以抑制疾病的发展。为了确定IL-4抑制疾病的能力是否依赖于IL-4介导的IL-12调节，我们评估了IL-4在调节PGIA发展中的需求。与野生型对照相比，缺乏IL-4和Stat6的小鼠用蛋白多糖免疫会导致关节炎严重程度显著增加，这表明关节炎严重程度是由IL-4通过Stat6依赖机制调节的。在IL-4（-/-）小鼠中，伴随着疾病的加重，全身促炎细胞因子IL-12、tnf - α和ifn - γ的产生以及关节中促炎细胞因子和趋化因子mRNA转录物的水平显著增加。Stat4（-/-）小鼠的疾病受到抑制，表明IL-12水平升高有助于关节炎的恶化，这种抑制伴随着ifn - γ产生水平的降低。为了支持这一点，ifn - γ(-/-)小鼠受到PGIA的保护，炎症程度与Stat4（-/-）小鼠相似。ifn - γ(-/-)和Stat4（-/-）小鼠疾病严重程度的降低与tnf - α水平的降低相关，但没有转换到th2型反应。综上所述，这些结果表明IL-4通过控制IL-12的产生来调节PGIA疾病的严重程度，而IL-12又通过stat4依赖的途径调节ifn - γ的表达量。
IL-4, a well-recognized modulator of macrophage activation, is perceived as an anti-inflammatory cytokine; however, under certain circumstances IL-4 may function as a proinflammatory cytokine. We have previously demonstrated that IL-4 treatment of mice with proteoglycan-induced arthritis (PGIA) inhibited the development of disease. To determine whether the capacity of IL-4 to inhibit disease is dependent on IL-4-mediated regulation of IL-12, we assessed the requirement for IL-4 in modulating development of PGIA. Immunization of mice, lacking IL-4 and Stat6, with proteoglycan results in a significant increase in arthritis severity in comparison to wild-type controls, suggesting that arthritis severity is regulated by IL-4 through a Stat6-dependent mechanism. Concomitant with exacerbated disease in IL-4(-/-) mice, there is a significant increase in the systemic production of proinflammatory cytokines IL-12, TNF-alpha, and IFN-gamma and in levels of mRNA transcripts for proinflammatory cytokines and chemokines in joints. Disease is suppressed in Stat4(-/-) mice indicating that elevated levels of IL-12 contribute to exacerbation of arthritis and that suppression is accompanied by reduced levels of IFN-gamma production. In support of this, IFN-gamma(-/-) mice are protected from PGIA and the degree of inflammation is similar to Stat4(-/-) mice. The decrease in disease severity in IFN-gamma(-/-) and Stat4(-/-) mice correlates with diminished TNF-alpha levels but there is no switch to a Th2-type response. Taken together, these results suggest that IL-4 regulates the severity of disease in PGIA by controlling IL-12 production, which in turn regulates the magnitude of IFN-gamma expression through a Stat4-dependent pathway.