**3.4. Natural killer cells (NKC)**

Total numbers of circulating NKC are not significantly altered following administration of GCs. But, sustained upregulation of NKC activation genes were observed [34].

### **3.5. Endothelial cells**

GCs have profound effects on the activation/function of endothelial cells and certainly inhibit vascular permeability. GCs inhibit directly the expression of adhesion molecules on both leukocytes and endothelial cells. GCs inhibit endothelial adhesion, as well as indirect effects due to the inhibition of transcription on cytokines (interleukin-1 and tumor necrosis factor) which upregulate endothelial adhesion molecule expression [25].

### **3.6. T lymphocytes**

Administration of the GCs causes a dramatic diminution of in vitro antigen responsiveness of T lymphocytes. The generation, proliferation, and function of helper and suppressor T cells and cytotoxic T cell responses are inhibited by GCs. These effects are due to the inhibition of the release of certain cytokines. GCs also inhibit the acute generation of both T helper type 1 and T helper type 2-derived cytokines by activated T cells. But the inhibitory effect on expression of T helper type 1-derived cytokines is greater [35–38].

### **3.7. B lymphocytes and immunoglobulin levels**

GCs have gradual effects on B cell activation, proliferation, and differentiation. B lymphocytes are relatively resistant to the immunosuppressive effects of GCs in contrast to T lymphocytes. Once B cells are activated, they differentiate into immunoglobulin-secreting plasma cells. But GCs have only minimal effects on this differentiation process. The most important effect of GCs on B lymphocytes relevant with immunoglobulin production and secretion. GCs also increase immunoglobulin catabolism. A short course of treatment with GCs causes an evident and permanent decrease in serum IgG. In contrast, immunoglobulin E (IgE) levels may increase. Whether GCs inhibit immunoglobulin gene expression is not known. Consequently, low-dose GCs inhibits leukocyte traffic and cellular immune responses. But to suppress the functions of leukocytes and the humoral immune response, higher doses of GCs are needed. This variability of drug response is also obvious among different patients and diseases [39–43].

### **3.8. Dendritic cells and antigen presentation**

GCs causes a significant reduction in circulating dendritic cells. Dendritic are the major stimulants of naïve T cells by presenting antigens. As a result, GCs impair the development of immunity to first encountered antigens [44].

### **3.9. Fibroblasts**

**3.3. Eosinophils, basophils, and mast cells**

98 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

**3.4. Natural killer cells (NKC)**

**3.5. Endothelial cells**

**3.6. T lymphocytes**

GCs support eosinophil apoptosis. In addition to this, GCs decrease the accumulation of eosinophils and mast cells to the allergic reaction sites. Also, GCs inhibit IgE-dependent release of histamine and leukotriene C4 from basophils, and they also inhibit degranulation both production of cytokines and degranulation of mast cells and eosinophils [26, 32, 33].

Total numbers of circulating NKC are not significantly altered following administration of

GCs have profound effects on the activation/function of endothelial cells and certainly inhibit vascular permeability. GCs inhibit directly the expression of adhesion molecules on both leukocytes and endothelial cells. GCs inhibit endothelial adhesion, as well as indirect effects due to the inhibition of transcription on cytokines (interleukin-1 and tumor necrosis factor) which

Administration of the GCs causes a dramatic diminution of in vitro antigen responsiveness of T lymphocytes. The generation, proliferation, and function of helper and suppressor T cells and cytotoxic T cell responses are inhibited by GCs. These effects are due to the inhibition of the release of certain cytokines. GCs also inhibit the acute generation of both T helper type 1 and T helper type 2-derived cytokines by activated T cells. But the inhibitory effect on expres-

GCs have gradual effects on B cell activation, proliferation, and differentiation. B lymphocytes are relatively resistant to the immunosuppressive effects of GCs in contrast to T lymphocytes. Once B cells are activated, they differentiate into immunoglobulin-secreting plasma cells. But GCs have only minimal effects on this differentiation process. The most important effect of GCs on B lymphocytes relevant with immunoglobulin production and secretion. GCs also increase immunoglobulin catabolism. A short course of treatment with GCs causes an evident and permanent decrease in serum IgG. In contrast, immunoglobulin E (IgE) levels may increase. Whether GCs inhibit immunoglobulin gene expression is not known. Consequently, low-dose GCs inhibits leukocyte traffic and cellular immune responses. But to suppress the functions of leukocytes and the humoral immune response, higher doses of GCs are needed. This variability of drug response is also obvious among different patients and diseases [39–43].

GCs causes a significant reduction in circulating dendritic cells. Dendritic are the major stimulants of naïve T cells by presenting antigens. As a result, GCs impair the development of

GCs. But, sustained upregulation of NKC activation genes were observed [34].

upregulate endothelial adhesion molecule expression [25].

sion of T helper type 1-derived cytokines is greater [35–38].

**3.7. B lymphocytes and immunoglobulin levels**

**3.8. Dendritic cells and antigen presentation**

immunity to first encountered antigens [44].

At supraphysiological concentrations, GCs suppress proliferation of fibroblasts and growth factor-induced DNA synthesis and protein synthesis, including synthesis of collagen and glycosaminoglycan. Also GCs have been shown to interact with two mediators of fibroplasia; transforming growth factor-β and vascular endothelial growth factor. Furthermore GCs induce fibronectin messenger RNA transcription, inhibit interleukin-1, tumor necrosis factor-αinduced metalloproteinase synthesis, and arachidonic acid metabolite synthesis [20, 28, 45, 46].

### **3.10. Prostaglandins**

Suppression of inflammatory prostaglandins (PGs) is a major factor in the anti-inflammatory action of the GCs. The suppression of phospholipase A2 activity with GCs is mediated by the activation of inhibitors of the enzyme itself or by inhibition of enzyme synthesis. The glucocorticoid-linked lipocortin/annexin family of proteins may be involved in this process. A second step in prostaglandin synthesis is the formation of prostaglandin H2 from arachidonic acid by enzymes called cyclooxygenases. The COX-2 gene and protein are strongly upregulated in endothelial cells, fibroblasts, and macrophages, and by mediators, such as endotoxin and interleukin-1. But GCs strongly suppress the expression of COX-2 induced by inflammatory stimuli. Later, D'Adamio et al. identified a glucocorticoid-induced leucine zipper (GILZ). GILZ is a member of the leucine zipper protein family which belongs to the transforming growth factor β-stimulated clone-22 family of transcription factors. GILZ inhibits inflammatory cytokine-induced expression of COX-2, by this way mediates the anti-inflammatory effects of GCs [47–53].
