**3. Secretion of anti-inflammatory factors by MSCs is regulated by pro-inflammatory cytokines**

To participate in tissue repair, MSCs must be in close association with several stromal and immune cells. The mode of action of MSC tissue repair is complex wherein MSC-derived immunoregulatory factors play a critical role.

MSCs are reported to release an array of growth factors and immunomodulatory molecules (**Table 1**).

To investigate how the inflammatory microenvironment modulated secretion of anti-inflammatory factors at the sites of tissue damage and it was concluded that MSC-mediated immunosuppression occurs in the microenvironment surrounding the MSCs: the inflammatory factors produced during the immune response act to turn on the immunosuppressive capacity of MSCs. For example, during pregnancy, the developed immunological tolerance along with the fetus development highlights the key role of fetus-derived MSCs. These pleotropic cells inhibit a group of cells involved in innate and adaptive immunity such as B cells, dendritic cells (DC), macrophages, and various effector cells such as NK, CD4+ T, CD8+ T, regulatory T (Treg), and NKT cells [33, 34]. The contribution of MSC-derived molecules toward the immunoregulation has been discussed (**Figure 3**).

#### **3.1 Indoleamine-2,3-dioxygenase (IDO)**

Indoleamine-2,3-dioxygenase is a mammalian cytosolic enzyme responsible for catalyzing the initial step in tryptophan catabolism via the kynurenine degradation pathways. IDO is comprised of two alpha helical domains with a heme group located between them and is an essential amino acid which catalyzes the ratelimiting step in the degradation of tryptophan, with the kynurenine pathway [35]. Any reduction in the concentration of local tryptophan or its metabolite results in immunomodulatory effect by IDO expressing cells.

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**Table 1.**

*Secretome profile of hMSCs and their functions.*

*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions*

*DOI: http://dx.doi.org/10.5772/intechopen.80772*

*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions DOI: http://dx.doi.org/10.5772/intechopen.80772*


**Table 1.**

*Secretome profile of hMSCs and their functions.*

*Immune Response Activation and Immunomodulation*

thymus, spleen, and liver [12, 24, 25].

**pro-inflammatory cytokines**

model [31, 32]*.*

molecules (**Table 1**).

the stem cells were provided by the recipient [24]. Therefore, a number of trials at both the preclinical and clinical levels have been carried out, and MSCs are seen to help migrate in a variety of tissues. Initial studies in animal models also confirmed that the presence of MSCs transplanted to donor was present in the bone marrow,

To elucidate the dynamics of MSCs migration, a systemic infusion of MSCs was studied by using varied techniques, i.e., after infusion of MSCs, they were first trapped in the lungs, and eventually, the cells disappear from the lungs and are distributed to other organs. Other aspects of MSCs homing was also studied by few groups under which they studied the factors such as early cell passage, irradiation and younger animals and observed that they influence the short-term bone marrow

Once MSCs are activated and recruited to the site of injury, there is onset of T-cell activation because of the presence of various pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1β, etc. IFN-γ is a critical player in providing stimulatory signals for activation and expansion of T cells and its subsets, such as it begins to suppress the T cell proliferation, differentiation, and inhibition of various biological functions. Other than IFN-γ, TNF-α and IL-1β also activate MSCs, either in synergy or alone. After stimulation with pro-inflammatory cytokines, MSCs also release other significant immunomodulatory factors. These stimulated cells modulate many immune effecters in vitro as well as in an animal

homing and condition which in result increases the homing [26–30].

**3. Secretion of anti-inflammatory factors by MSCs is regulated by** 

wherein MSC-derived immunoregulatory factors play a critical role.

the immunoregulation has been discussed (**Figure 3**).

immunomodulatory effect by IDO expressing cells.

**3.1 Indoleamine-2,3-dioxygenase (IDO)**

To participate in tissue repair, MSCs must be in close association with several stromal and immune cells. The mode of action of MSC tissue repair is complex

MSCs are reported to release an array of growth factors and immunomodulatory

To investigate how the inflammatory microenvironment modulated secretion of anti-inflammatory factors at the sites of tissue damage and it was concluded that MSC-mediated immunosuppression occurs in the microenvironment surrounding the MSCs: the inflammatory factors produced during the immune response act to turn on the immunosuppressive capacity of MSCs. For example, during pregnancy, the developed immunological tolerance along with the fetus development highlights the key role of fetus-derived MSCs. These pleotropic cells inhibit a group of cells involved in innate and adaptive immunity such as B cells, dendritic cells (DC), macrophages, and various effector cells such as NK, CD4+ T, CD8+ T, regulatory T (Treg), and NKT cells [33, 34]. The contribution of MSC-derived molecules toward

Indoleamine-2,3-dioxygenase is a mammalian cytosolic enzyme responsible for catalyzing the initial step in tryptophan catabolism via the kynurenine degradation pathways. IDO is comprised of two alpha helical domains with a heme group located between them and is an essential amino acid which catalyzes the ratelimiting step in the degradation of tryptophan, with the kynurenine pathway [35]. Any reduction in the concentration of local tryptophan or its metabolite results in

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#### **Figure 3.**

*Representative image shows the immune response of MSCs by secretion of IM factors (left panel). Immunoregulatory function of MSCs on different cell types of the innate and adaptive immune cells. (Right panel) paracrine effect of MSCs through secretion of exosomes and their fusion with the target cell membrane and release of the biological active content for immunomodulatory effect.*

The studies carried out with placental cells showed that they are capable of preventing maternal T-cell destruction of the fetus during pregnancy, which happens due to the expression of IDO in placental cells. During pregnancy, the fetus expresses paternal antigens that do not provoke rejection by the mother like other semi-allogeneic grafts [36, 37]*.* Dendritic cells can also express IDO and thus induce a tolerogenic response. Su et al. suggest that MSCs do not have the innate ability to express IDO but gain this ability following stimulation by the pro-inflammatory cytokines IFN-γ and TNF-α in combination with IL-1β [38]. Recently, the role of IDO in MSC-mediated immunoregulation has been demonstrated in the suppression of various immune cell populations, including T cells and NK cells [39, 40].

#### **3.2 Human leukocyte antigen-G (HLA-G)**

HLA-G is a major histocompatibility complex class I antigen encoded by a gene on chromosome 6p21. It differs from classical HLA class I molecules by its restricted tissue distribution and limited polymorphism in the coding region. HLA-G can be expressed as seven distinct protein isoforms, each encoded by a specific, alternatively spliced transcript. Four isoforms are membrane-bound proteins (HLA-G1, HLA-G2, HLA-G3, and HLA-G4), and the other three isoforms are soluble proteins (HLA-G5, HLA-G6, and HLA-G7) [41]. It exerts its immunomodulatory functions by interacting with multiple receptors such as LILRB1(ILT2/ CD85j), LILRB2 (ILT4/CD85d), and KIR2DL4 (CD158d) which are differentially expressed by immune cells. Besides these receptors, HLA-G can also bind to CD8 without T-cell receptor (TCR) interaction, provoking NK cells and activated CD8 + T cell-induced apoptosis as well as FASL upregulation and secretion [42, 43]. HLA-G plays a fundamental role in maternal tolerance and transplantation. HLA-G expression by MSCs can be positively modulated by IL-10 and leukemia inhibitory factor (LIF). Other molecules such as glucocorticoid and interferon-β (IFN-β) are found to regulate HLA-G expression in immune cells. HLA-G has been

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*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions*

investigated for allogeneic solid organ transplantation and has been well associated with reduced number of immune rejection cases in kidney and liver allogeneic

Prostaglandins are small molecule derivatives of arachidonic acid (AA), produced by cyclooxygenase (COX, constitutively active cyclooxygenase COX1 and inducible COX2) and PG synthases. It can be produced by all cell types of the body, with epithelia, fibroblast, and infiltrating inflammatory cells representing the major sources of PGE-2 in the course of an immune response. The receptors of PGE2 (EP1–EP4) are present on multiple cell types, reflecting the ubiquitous function of PGE-2. It is relatively stable in vitro although its decay is accelerated by albumin [46]. In contrast, PGE-2 has a very rapid throughput rate in in vivo conditions and is quickly eliminated from tissues and circulation. This property of PGE-2 is most likely to contribute toward immune pathology and constitutes a potential target for immunomodulation. It is worth noting that the effect of PGE-2 in MSCmediated immunoregulation in most cases is exerted in combination with other immunosuppressive molecules. With human MSCs, PGE-2 has been found to act with IDO to alter T-cell proliferation, during proliferation, cytotoxicity, and

Nitric oxide synthases are family of enzymes catalyzing the production of nitric oxide from L-arginine. The enzymes convert arginine into citrulline and produce NO in the process. NO activity is independent of the level of calcium in the cell. However, its activity as other NO isoforms is dependent upon the binding of calmodulin (CaM). NO in high concentration is known to inhibit immune responses through mechanisms that remain largely unidentified. In addition, upon induction cytokines such as TNF-α and IFN-γ, alone or in combination, stimulate NO. This has a significant impact on both primary and secondary immune responses. For example, NO targets dendritic cells (DCs) that have a crucial role in making powerful immune response. It was found to prevent maturation of rat lung DCs by inhibiting granulocyte-macrophage colony-stimulating factors. Similarly, NO inhibits TNF-α and prevents DC maturation in humans [48]. MSCs produce large amounts of chemokines and adhesion molecules; immune cells accumulate in close proximity to the MSCs, where the high concentration of secreted NO can suppress

IL-10 is produced by both myeloid and lymphoid cells. While it is good immune

suppressor, it has some immune stimulatory effects. IL-10 is recognized by its effect on T cells, macrophages, and monocytes which ultimately prohibit inflammatory responses. Thus, it regulates growth and differentiation of B cells, T cells, NK cells, and other cells of the immune system hence influencing inflammatory responses. IL-10 has the capability to inhibit the production of IL-2, TNF-α, IL-12, and IFN-γ. Furthermore, it will downregulate HLA class I. Although IL-10 has been implicated in MSC-mediated immunosuppression, direct IL-10 production by MSCs has not been demonstrated so far. Instead, contact of antigen-presenting cells such as dendritic cells or monocytes with MSCs has been found to induce

*DOI: http://dx.doi.org/10.5772/intechopen.80772*

transplantations [44, 45].

**3.3 Prostaglandin E2 (PGE-2)**

cytokine production by NK cells [47].

the immune cells [49, 50].

**3.5 Interleukin 10 (IL-10)**

IL-10 production [51–53].

**3.4 Inducible nitric oxide synthase (iNOs)**

*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions DOI: http://dx.doi.org/10.5772/intechopen.80772*

investigated for allogeneic solid organ transplantation and has been well associated with reduced number of immune rejection cases in kidney and liver allogeneic transplantations [44, 45].
