**3. Clinical relevance of lactoferrin**

Lactoferrin is a versatile molecule that has been molded by natural selection to be amongst the first line of defense in mammals [25]. As the second most abundant protein in colostrum, it is responsible for conferring immunity on newborns within the first few weeks of life [26]. Lactoferrin is involved in various physiological functions such as regulating homeostasis and cell proliferation, besides being a very potent antimicrobial agent. It has antibacterial, antifungal, antiviral, antioxidant, immunomodulatory, and anticancer activities [25, 27–29]. During infection and inflammation processes, the lactoferrin concentration increases through the recruitment of neutrophils. The important properties of lactoferrin have been depicted in the flow diagram in **Figure 1**.

Lactoferrin, the natural protein, is proving to be a highly promising bio-drug as an antimicrobial, immunomodulatory, and anticancer agent. According to Cragg *et al.,* over 50% of the drugs in clinical trials for anticancer activity are isolated from natural sources or their ingredients. Several drugs currently used in chemotherapy are isolated from plant species and food sources [30, 31] Lactoferrin is a multi-functional protein with many beneficial properties. It is now recognized as a functional food for several products with commercial and clinical applications [32]. It is widely distributed in all biological fluids and is also expressed by immune cells, which release it under stimulation by pathogens.

The primary function of lactoferrin has been recognized to be in the modulation of the immune responses, besides iron transport, storage, and chelation. Lactoferrin activates immune cells and enhances their proliferation and differentiation. Its potential to perform multiple activities is often attributed to its capacity to bind iron and interact with diverse molecular and cellular components of hosts and pathogens. The multiple functions ascribed to lactoferrin can either be dependent or independent of lactoferrin's iron-binding ability [33]. Furthermore, it is noteworthy that lactoferrin concentrations are locally elevated in inflammatory disorders such as neurodegenerative diseases, autoimmune diseases (e.g., arthritis), and allergic inflammation.

#### **3.1 Lactoferrin as an Immuno-modulator**

Lactoferrin is a cell-secreted mediator that bridges innate and adaptive immune responses. For immune-modulatory functions, it interacts with specific receptors of the target cells (either epithelial cells or cells of the immune system) It also can bind to bacterial cell wall LPS. Lactoferrin modulates the activation, proliferation, maturation, differentiation, and migration of immune cells. The functional modulations take place in the T and B cells, neutrophils, monocytes/macrophages, and dendritic cells belonging to the antigen-presenting class of cells. It acts via two mechanisms of intracellular signal transduction, *i.e.,* nuclear factor kappa B and MAP kinase [34–36]. Furthermore, it affects the mechanisms of the innate response, by influencing the activation of the complement system, increasing the NK cell activity, increasing the phagocytic ability of monocytes, and by enhancing their cytotoxicity [37]. There are lactoferrin receptors on many immune cells, so lactoferrin directly affects how these cells function. Its action increases levels of cytokines such as tumor necrosis factor (TNF-alpha), interleukin 8 (IL-8), and Nitric Oxide production besides limiting pathogenic growth [37, 38].

Lactoferrin modulates innate and adaptive immune response because of its ability to bind LPS and CD-14. It also interferes with the formation of the CD14–LPS complex. This results in the attenuation of the LPS/CD-14/TLR-4, a signaling pathway involved in the pathogenesis of sepsis. Lactoferrin may stimulate the immune system by binding to CD-14 and then activating the TLR-4-mediated pathway while preventing overexpression of LPS-induced inflammation [39]. Lactoferrin, which functions as a natural iron scavenger and a modulator of signaling pathways, leads to the negative feedback of the inflammatory response. This is also shown by a decrease in the production of reactive oxygen species and various pro-inflammatory cytokines [40].

### *Medicinal Potential of Camel Milk Lactoferrin DOI: http://dx.doi.org/10.5772/intechopen.108316*

In addition to this, researchers have shown that in a murine model of diethyl nitrosamine-induced hepatocarcinogenesis, bovine milk lactoferrin significantly down-regulated the activity of liver antioxidant enzymes such as glutathione peroxidase, superoxide dismutase and catalase. It also increased the concentration of hepatic glutathione. Furthermore, bovine lactoferrin promoted the decrease of serum inflammatory markers and ameliorated in hepatic histological structures in a significant manner [41]. Furthermore, the applications of lactoferrin have been highlighted in **Table 2**.

Other than the direct modulation of the immune response, lactoferrin strategically acts as a potent anti-inflammatory agent by scavenging ROS. Pro-oxidant agents can both promote DNA damage and induce as well as sustain inflammatory disorders. Inflammation itself drastically contributes to cancer development. Lactoferrin can maintain the physiological balance of ROS levels by direct binding of free iron, one of the principal actors involved in ROS production. It can also act as a regulator of key antioxidant enzymes, thus protecting the host from ROS-mediated cell and tissue damage in an overall manner [51].

The protective character of lactoferrin against cancer has been demonstrated, on numerous occasions, including its impact on chemically induced tumors, in laboratory rodents. Lactoferrin has even been reported to inhibit the development of experimental metastases in mice [52–54]. Lactoferrin-mediated inhibition of tumor growth might be related to apoptosis of these cells, induced by the activation of the Fas signaling pathway. Nevertheless, the exact mechanism of this function has not been discovered so far [55].
