Previous clinical study has revealed the elevation of plasma IL-17 concentration in patients with allergic asthma (Wong, Ho, Ko, Chan, Ho, Hui, Lam 2001). In animal studies, intranasal administration of IL-25 in mice induces the production of Th2 cytokines IL-4, IL-5, and IL-13 in the lung (Hurst, Muchamuel, Gorman, Gilbert, Clifford, Kwan, Menon, Seymour, Jackson, Kung, et al. 2002). IL-4 and IL-5 are crucial for the local infiltration and activation of eosinophils (Giembycz, & Lindsay 1999). IL-13 induces airway hyperreactivity, increased mucus secretion and allergic inflammation.
Eosinophils are the most important inflammatory effector cells accumulating at the site of allergic inflammation such as allergic asthma. The activated eosinophils release cytokines such as interleukin (IL)-3, IL-4, IL-5, IL-6, IL-16 that cause tissue damage and consequently the manifestation of allergic diseases. Therefore, IL-25 plays an important role in signaling the immune system and provoking allergic inflammation, especially eosinophil-mediated late phase allergic reactions Cheung, Wong & Lam 2005).
To explore the intracellular mechanisms caused by the introduction of IL-25, the activation of intracellular signaling molecules such as mitogen-activated protein kinases (MAPKs) are examined. MAPKs have been proved to control the majority of inflammatory responses in allergic diseases. A number of MAPK inhibitors have been developed into therapeutic drugs to suppress the activation of these signaling pathways (Wong, Lam 2004). MAPKs respond to the stimuli of mitogens. Mitogen is some form of a protein that encourages a cell to start a number of cell activities such as mitosis, differentiation, gene expression, and cell survival.
Mitosis is the process of cell division to generate two identical cells by dividing the cytoplasm and the cell membrane to result in two identical cells with equal distribution of organelles. Differentiation is a process by which a cell acquires a type by losing its unspecialized status to become a specialized cell such as heart, liver, or muscle cell. There are mainly three kinds of MAPK: p38 isoforms, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERKs).
The most prominent of the MAPKs involved in the inflammatory response are those of the p38 subfamily, but other subgroups such as c-jun NKs and ERKs are also involved. IL-25 operates by activating Mitogen-activated protein kinases (MAPK) pathways in lymphocytes via a receptor known as IL-17BR, which is strongly expressed in B cells after activation by CD-40 and other Th2 inflammation factors. MAPKs are highly conserved intracellular enzymes which are involved in signal transduction in several metabolic pathways.
To determine whether IL-25 activates other intracellular signaling pathways such as MAPK pathways, Maezawa, Nakajima, Suzuki, Tamachi, Ikeda, Inoue, Saito, & Iwamoto (2006) experimented on the effect of IL-25 on activation of MAPK. They examined the phosphorylation of ERK, JNK, and p38 upon stimulation of IL-25. The phosphorylation of ERK was markedly induced upon stimulation at similar levels to that induced by IL-17. The phosphorylation of JNK and p38 was also induced but weaker than that induced by IL-17. Their results have concluded that IL-25 activates ERK, JNK, and p38 pathways.