Therapeutic target validation of protein kinase C(PKC)-ζ for asthma using a mouse model

Protein kinase C (PKC) is a complex family consisting of many types of isoenzymes, of which PKC-ζ, an atypical isoform, has been reportedly implicated in the regulation of apoptosis and NF-κB, as well as control of T-dependent responses. Based on the recent report that PKC-ζ controls TH2 response, the current study was aimed to evaluate PKC-ζ 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-ζ pseudosubstrate inhibitor (PPI) was intratracheally instilled before each OVA challenge. Airway hyperreactivity (AHR) was measured by β-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-ζ activation alleviates asthmatic manifestations. Additionally, PPI instillation decreased IL-5 and IL-13 levels in BALF to approximately 20% of controls, but not IFN-γ level. Instillation of PPI also caused a marked fall in the level of TNF-α, another NF-κB-dependent, proinflammatory cytokine. Serum OVA-specific IgE level and ex vivo IL-4, IL-5 and IL-13, but not IFN-γ, production by peribronchial lymph node cells was also considerably lower in PPI-treated mice. In conclusion, blockade of PKC-ζ signals by intratracheal instillation of PPI alleviates allergen-specific TH2 response as well as asthmatic manifestations and hence PKC-ζ is a promising target for treatment of asthma.