**7.1 Antimicrobial activities**

HBD2 has a broad spectrum of activity against a wide variety of bacteria, fungi and viruses. The mechanism of action of this defensin begins with the interaction of the negative charges of the pathogen membrane, the formation of pores and finally the lysis of the microorganism. The variability of the composition of the membranes of the different pathogens explains in part the different antimicrobial effects [2, 22].

#### **7.2 Innate and adaptive immunity**

HBD2 is important in innate immunity and constitutes the first line of host defense against infections by microorganisms. Its role in adaptive immunity is attributed mainly to its chemotactic activity in immature dendritic cells and memory T lymphocytes through the CCR6 receptor [26].

Several mechanisms have been proposed for HBD2 that contributes to the adaptive immunity: (a) Increase in the recruitment of immature dendritic cells. Immature dendritic cells are recruited from circulating blood or tissue near the site of inflammation by chemoattractants that interact with their corresponding receptors (CCR1, CCR5, CCR6). (b) Formation of defensin-antigen complexes. HBD2 forms defensin-antigen complexes facilitating the presentation to dendritic cells. (c) Maturation of dendritic cells. HBD2 induced the maturation of dendritic cells for direct production of IL-2 or indirect production of TNF and IL-1 by monocytes and macrophages. (d) Recruitment of memory T cells. It facilitates the recruitment of memory T cells that are the effector cells of adaptive immunity [15, 26].

HBD2 contributes to unite the innate and adaptive immune response, and this property has been applied for the development of vaccine adjuvants, since it promotes adaptive immunity when it is administered together with antigens [15, 26].

### **7.3 Inflammation**

Inflammation is a protective reaction by the host to eliminate injurious stimuli (microorganism, damage cell or irritants). Some viral infections cause severe inflammation, and the tissue can be damaged and then it must be repaired. The mechanisms include the production of anti-inflammatory cytokines, lipid mediators, glucocorticoids, immune cell apoptosis, etc. [3].

HBD2 plays a critical role in regulating inflammation processes in the respiratory system and modulates the production of inflammatory cytokines and chemokines. An increase in local expression has been observed; but in severe cases, the HBD2 can be detected systemically [71].

HBD-2 can promote histamine release and prostaglandin D2 production in mast cells, suggesting a role in allergic reactions [1, 26, 72].

#### **7.4 Anti-inflammatory activity**

HBD2 and the complement system are two important innate immune mechanisms against a broad range of microorganisms. The complement is composed of more than 30 proteins found in the human serum, and it is activated by three different pathways (classical, alternative and lectin) [73, 74]. It has been described that HBD2 binds to C1q (first component of the complement system) and inhibits the classical complement pathway. HBD2 have a dual protective role not only as an antimicrobial agent but also to provide protection against uncontrolled activation of complement system [73, 75, 76].

**59**

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections*

Recently, the study of the HBD2 has focused on the modulation of the immune response. It has been suggested that multiple mechanisms of action may be involved from direct binding to the membrane of the microorganism to the union with different types of cellular receptors that can induce transduction signals, gene transcription and various signaling pathways [77]. This mechanism paves the way

In a study with epithelial lung cells (A549) stimulated with LPS, it was demonstrated that the association of moxifloxacin/HBD2 has an anti-inflammatory effect. Moxifloxacin is a fluoroquinolone against Gram-positive and Gram-negative bacteria, which may have affected the immune system. The treatment induced a reduction of proinflammatory cytokines (IL-1 and IL-6). These data support the hypothesis of its immunomodulatory capacity of HBD2 to neutralize the compo-

VitD plays an important role for the calcium homeostasis in the bones. Currently, the interest has focused on the modulation of the immune response in fighting viral respiratory infections. Some studies show that patients with deficiencies in VitD are at higher risk of suffering respiratory infections in the upper respiratory tract [79]. One study showed the association of polymorphisms in the VitD receptor and severe bronchiolitis in patients infected by the respiratory

The immunomodulatory effect has been of great importance in some viral infections; several types of cells including epithelial cells treated with VitD induce the expression of the receptor and the production of antimicrobial peptides such as the HBD2. In the patients infected with HIV, the high levels of VitD and its receptor increase the amount of IL-10 and HBD2, which are associated with a natural

The VitD receptor is expressed in several types of cells (monocytes, B cells, T cells and NK), is an endogenous immunomodulator and induces the transcription of the HBD2. This work shows that the expression of HBD2 is important to render

It is a family of receptors coupled to the G-protein, which is formed by seven transmembrane domains with an amino-terminal extracellular domain and a C-terminal domain. PARs are activated by proteolytic cleavage in the N-terminal domain by serine proteases. N-terminal serves as a ligand to carry out intracellular signaling. They are expressed in epithelial, endothelial and immune cells such as leukocytes, mast cells, eosinophils, neutrophils and mastoid cells. Four types of receptors have been described (PAR-1–4). PAR-1, 3 and 4 are activated mainly by thrombin and are involved in the aggregation of platelets. PAR-2 is activated by trypsin, tryptase from mastoid cells, protease 3 from neutrophils and tissue factor, factor VIIa and Xa [81]. Recently, PARs have been implicated in the regulation of the expression of antimicrobial peptides found in epithelial cells such as defensins [65, 82]. The researchers identified the expression of the HBD2 in human

for the development of new therapies for infectious respiratory diseases.

nents of bacteria that induce the activation of cytokines [78].

*DOI: http://dx.doi.org/10.5772/intechopen.80611*

**7.5 Immunomodulatory properties**

*7.5.1 Moxifloxacin/HBD2*

*7.5.2 Vitamin D (VitD)*

syncytial virus [80].

resistance to HIV infection [62].

tolerance to viral infections [62, 64].

*7.5.3 PARs (receptors coupled to proteases)*
