Do Jeong-Su, Park Kang-Seo, Seo Hyo-Jung, Kim Jun-Hee, Hwang Jin-Ki, Song Eun-Jung, Nam Sang-Yun
Department of Biological Science, School of Science and Technology, Jeonju University, Jeonju 560-759, Korea.
Int J Mol Med. 2009 Apr;23(4):561-6.
Protein kinase C (PKC) is a complex family consisting of many types of isoenzymes, of which PKC-zeta, an atypical isoform, has been reportedly implicated in the regulation of apoptosis and NF-kappaB, as well as control of T-dependent responses. Based on the recent report that PKC-zeta controls TH2 response, the current study was aimed to evaluate PKC-zeta as a potential therapeutic target for asthma using a mouse model. Mouse allergic asthma was induced by repeated sensitization followed by intranasal challenge with OVA and PKC-zeta pseudosubstrate inhibitor (PPI) was intratracheally instilled before each OVA challenge. Airway hyperreactivity (AHR) was measured by beta-methacoline-induced airflow obstruction. Cellular and cytokine profile in bronchoalveolar lavage fluid (BALF) and level of serum IgE as well as cytokine production by draining lymph node cells were compared. AHR and numbers of eosinophils in BALF were significantly lowered by PPI, indicating that blocking of PKC-zeta activation alleviates asthmatic manifestations. Additionally, PPI instillation decreased IL-5 and IL-13 levels in BALF to approximately 20% of controls, but not IFN-gamma level. Instillation of PPI also caused a marked fall in the level of TNF-alpha, another NF-kappaB-dependent, proinflammatory cytokine. Serum OVA-specific IgE level and ex vivo IL-4, IL-5 and IL-13, but not IFN-gamma, production by peribronchial lymph node cells was also considerably lower in PPI-treated mice. In conclusion, blockade of PKC-zeta signals by intratracheal instillation of PPI alleviates allergen-specific TH2 response as well as asthmatic manifestations and hence PKC-zeta is a promising target for treatment of asthma.
蛋白激酶C（PKC）是一个由多种同工酶组成的复杂家族，其中非典型同工型PKC-ζ据报道与细胞凋亡和核因子κB的调节有关，也参与T细胞依赖性反应的调控。基于最近关于PKC-ζ控制TH2反应的报道，本研究旨在利用小鼠模型评估PKC-ζ作为哮喘潜在治疗靶点的可能性。通过反复致敏，随后用卵清蛋白（OVA）进行鼻内激发诱导小鼠过敏性哮喘，并在每次OVA激发前经气管内滴注PKC-ζ假底物抑制剂（PPI）。通过β-甲基胆碱诱导的气流阻塞来测量气道高反应性（AHR）。比较支气管肺泡灌洗液（BALF）中的细胞和细胞因子谱、血清IgE水平以及引流淋巴结细胞产生的细胞因子。PPI可显著降低AHR和BALF中嗜酸性粒细胞的数量，表明阻断PKC-ζ激活可减轻哮喘表现。此外，滴注PPI可使BALF中IL-5和IL-13水平降至对照组的约20%，但对IFN-γ水平无影响。滴注PPI还导致另一种核因子κB依赖性促炎细胞因子TNF-α水平显著下降。在PPI处理的小鼠中，血清OVA特异性IgE水平以及支气管周围淋巴结细胞体外产生的IL-4、IL-5和IL-13，但不包括IFN-γ，也显著降低。总之，经气管内滴注PPI阻断PKC-ζ信号可减轻变应原特异性TH2反应以及哮喘表现，因此PKC-ζ是治疗哮喘的一个有前景的靶点。
