The epidermis

also contains some immune cells, including Langerhans cells and CD8+ T cells, while the underlying dermis exhibits a more complicated histology due to the presence of a variety of immune cells, such as CD4+ Th cells, MΦs, and DC, in addition to fibroblasts 1. CD4+ Th cells can be classified into at least four subsets: Th1, Th2, Th17, and Treg, which coordinate immunity selleck screening library by producing unique sets of cytokines 2, 3. They are derived from naïve CD4+ T cells through exposure to specific cytokines and antigen presentation by DC 1, 3. IFN-γ and IL-4 promote the development of Th1 and Th2 cells, respectively, and Th1 and Th2 cells produce IFN-γ and IL-4, respectively, as their signature cytokines. On the other hand, Th17 cells are derived in the presence of TGF-β plus IL-6 for mice or TGF-β plus IL-21 for humans and produce IL-17 3, 4. They also produce IL-22 when

stimulated with IL-23 4. High concentration of TGF-β results in induction of the transcription factor Foxp3 and promotes the development of Treg, ACP-196 nmr which negatively regulate immune responses through production of IL-10 3, 5. Deregulated cytokine production in the skin leads to inflammatory diseases exemplified by psoriasis and atopic dermatitis in humans, which are T-cell-mediated skin diseases with unknown origin 6, 7. Cytokines derived from Th1 and Th17 cells are implicated in the pathogenesis of psoriasis, while those from Th2 cells are implicated in the pathogenesis of atopic dermatitis 8, 9. Moreover, cytokines derived from keratinocytes are recognized to have an important pathogenic role. For

instance, IL-23 is highly produced by epidermal keratinocytes as well as by Langerhans cells, dermal DC, and MΦs 10, and is implicated in the pathogenesis of psoriasis 1, 7. In addition, keratinocytes release not only chemokines exemplified by CC chemokine ligand (CCL)-20, a chemoattractant for DC precursors 11, but also a large amount of peptides exemplified by LL-37 12 and S100A7 (also known as psoriasin) 13, which are implicated not in the pathogenesis of psoriasis. Phosphoinositide-specific phospholipase C (PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate into two vital second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, thereby playing a pivotal role in intracellular signaling. There are six families of mammalian PLC isoforms (β, γ, δ, ε, ζ,and η) 14. PLCε was first identified by others and us as a direct downstream effector of Ras family small GTPases: Ras, Rap1, and Rap2 14, 15. In the skin, PLCε is expressed in resident skin cells but not in leukocytes 16–18. By using PLCε−/− mice, in which PLCε was inactivated by gene targeting, we showed that PLCε plays a crucial role in cutaneous carcinogenesis and inflammation.