Sen Pradip, Bhattacharyya Sandip, Wallet Mark, Wong Carmen P, Poligone Brian, Sen Maitreyee, Baldwin Albert S, Tisch Roland
Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
J Immunol. 2003 Feb 15;170(4):1770-80. doi: 10.4049/jimmunol.170.4.1770.
Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing beta cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-kappaB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-kappaB and its role in regulating the APC function of macrophages (Mphi) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mphi prepared from NOD mice exhibited increased NF-kappaB activation relative to NOR and BALB/c Mphi. This hyperactivation was detected for different NF-kappaB complexes and correlated with increased IkappaBalpha degradation. Furthermore, increased NF-kappaB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mphi to secrete IL-12(p70), TNF-alpha, and IL-1alpha, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IkappaBalpha. In contrast, elevated NF-kappaB activation had no significant effect on the capacity of NOD Mphi to stimulate CD4(+) or CD8(+) T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mphi exhibit hyperactivation of NF-kappaB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-kappaB influences Mphi APC function by regulating cytokine secretion but not T cell stimulation.
1型糖尿病的特征是慢性炎症反应，导致产生胰岛素的β细胞被选择性破坏。我们之前已经证明，从非肥胖糖尿病（NOD）小鼠（一种自发性1型糖尿病模型）制备的树突状细胞（DC）与非糖尿病品系小鼠的DC相比，表现出NF-κB的过度激活，导致分泌促炎细胞因子和刺激T细胞的能力增强。在当前研究中，研究了NF-κB的激活状态及其在调节从NOD、非肥胖抗性（NOR）和BALB/c小鼠制备的巨噬细胞（Mphi）的抗原呈递细胞（APC）功能中的作用。与刺激无关，从NOD小鼠制备的脾源性和骨髓源性Mphi相对于NOR和BALB/c Mphi表现出增强的NF-κB激活。在不同的NF-κB复合物中检测到这种过度激活，并且与IκBα降解增加相关。此外，NF-κB激活增加导致NOD与NOR或BALB/c Mphi相比分泌IL-12（p70）、TNF-α和IL-1α的能力增强，在用编码IκBα修饰形式的腺病毒重组体感染后这种能力受到抑制。相反，NF-κB激活升高对NOD Mphi以抗原特异性方式刺激CD4(+)或CD8(+) T细胞的能力没有显著影响。这些结果表明，除了NOD DC外，NOD Mphi也表现出NF-κB的过度激活，这与介导促炎反应的能力增加相关。此外，NF-κB通过调节细胞因子分泌而不是T细胞刺激来影响Mphi的APC功能。
