**5. Expression and regulation of β-defensin-2**

HBD2 is expressed mainly in all the epithelia of human body (respiratory, digestive, urogenital, conjunctive epithelium), mucous, peripheral blood and skin. In the respiratory system, HBD2 is expressed in mucous from the mouth to the epithelium of the lungs and is induced by bacteria, fungi and virus infections and by proinflammatory stimuli such as interleukin 1α (IL-1α), interleukin 1β (IL-1β), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and interleukin IL-6 (IL-6) [29, 47–51]. Recently, a study showed that the cytokines IL-17 and IL-22 are produced by Th17 cells, which are reportedly known to regulate the expression of HBD2 on mucosal surfaces [32]. HBD2 is produced as a functionally inactive peptide (prepro-defensin), and to achieve its biological activity, it must go through a post-translational modification process and form a mature peptide. Prepro-defensin is composed of a highly hydrophobic pre-peptide signal, a propeptide and the mature peptide. The prepropeptide is cut by proteases in the Golgi apparatus, and once removed, the mature peptide with antimicrobial activity is secreted on the surface of the epithelial cells [3, 52].

The regulation of the expression of the HBD2 in the respiratory epithelium involves multiple signaling pathways; most of these have been studied with bacterial infections. The bacterial proteins induce the expression of HBD2 in the respiratory epithelium through transcription factors (NF-kB) [53], the myeloid ELF-1-like factor (MEF) [54], the nuclear factor interleukin 6 (NF-IL6) [55] or the activated protein 1–3 (AP1–3) [56]. Signaling pathways involve mitogen-activated protein kinase (MAPKs) [49, 57, 58], phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) [59].

Another form to induce HBD2 expression is through cellular receptors, the respiratory epithelium expresses various receptors on its surface. Toll-like receptors (TLRs) 1–6 are expressed on the epithelial surface, and in the intracellular vesicles, the TLR3 and TLR7–9 are expressed in the endosomes or endoplasmic reticulum. These receptors recognize pathogens and have a cytoplasmic domain that is homologous to the IL-1 receptor and is responsible for initiating intracellular signaling pathways. This signaling cascade includes the activation of NF-kB. This transcription factor promotes the gene expression that contributes to the cytokines, chemokines, adhesion molecules, co-stimulatory molecules release as well as the expression of HBD2 [60].

In a study with lung epithelial cells infected with *L. pneumophila*, it was observed that the infection induces the release of HBD2, and its expression is mediated by the receptors TLR2 and TLR5 and activation of MAPKs (p38, JNK) and transcription factors NF-kB and AP-1 [50, 57, 58, 61].

Another way to regulate the expression of HBD2 is through the interaction with receptors; its chemotactic property was initially discovered in different types of cells such as monocytes, T cells and immature dendritic cells. The activity is carried through the CCR6 receptor binding [32].

Other receptors involved in the regulation of the HBD2 expression are the receptors for vitamin D and protease-coupled receptors (PARs) [62–65].

Nowadays, HBD2 is considered a multifunctional molecule; the ability to bind to several ligands suggests that there may be more receptors and signaling pathways still to be discovered and that may have important biological activities in the immune system.
