Peripheral blood monocytes

A new generation of antiinflammatory agents having immunosuppressive activity has been developed. The appearance of preclinical and clinical reports suggest that these are near entry to the pharmaceutical market. For example, tenidap (CP-66,248) (12) has been demonstrated to inhibit IL-1 production from human peripheral blood monocytes in culture (55). Clinically, IL-1 in synovial fluids of arthritic patients was reduced following treatment with tenidap. Patients with rheumatoid or osteoarthritis, when treated with tenidap, showed clinical improvement (57,58). In addition to its immunological effects, tenidap also has an antiinflammatory profile similar to the classical NSAIDs (59). Other synthetic inhibitors of IL-1 production are SKF 86002 (20) andE-5110 (21) (55). 

White blood cell preferentially located near potential entry sites for microbial pathogens and specialized for the uptake of particulate material by phagocytosis. Most macrophages originate from peripheral blood monocytes and are able to leave the circulation following stimulation by chemotactic agents. 

ROM production by peripheral blood monocytes Production of ROM by peripheral blood monocytes in response to a variety of stimuli is increased in patients with active IBD (Table 10.2), su esting that such cells may respond to local stimulants within the gut more readily than in normal subjects or those with quiescent disease, and so may play a role in perpetuating the inflammatory response, cent studies have su ested that peripheral blood monocytes in Crohn s disease may be primed by the baaerial cell wall products LPS and peptidoglycanpolysaccharide (Muraki et al., 1992). 

Muraki, T., Fu, R.D., Kazoroski, L., Baldassano, R.N., Ber-tovich, M.J., Izutan, R., Schreiber, S., Lichtenstein, G.R., Sartor, R.B. and MacDermott, R.P. (1992). Crohn s disease peripheral blood monocytes are primed by bacterial cell wall products for enhanced oxygen radical production. Gastroenterology 102, A668. 

Okabe, N., Kuriowa, A., Fujita, K., Shibuya, T., Yao, T. and Okumura, M. (1986). Immunolt cal studies on Crohn s disease. (vi) Increased chemiluminescent response of peripheral blood monocytes. J. Clin. Lab. Immunol. 21, 11-15. 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

Nucleic acid extraction protocols using guanidine hydrochloride, sodium sarco-syl, and ethanol have been developed to quantify viral RNA by bDNA in lymph node tissue, liver tissue, and peripheral blood monocytes (Wilber and Urdea, 1995). 

Figure 9.5 Healthy volunteer monocytes after erythrophagocytosis. Rabbit erythrocytes were incubated with heat-inactivated mouse antirabbit erythrocyte serum. Human peripheral blood monocytes (MN) were obtained after Ficoll-Paque isolation and monocyte clumping with subsequent separation from lymphocytes, yielding a 95 % pure MN population. Non-ingested erythrocytes were removed by hypotonic lysis.

Sakurai, T., Ohta, T., and Fujiwara, K., Inorganic arsenite alters macrophage generation from human peripheral blood monocytes, Toxicol. Appl. Pharmacol., 203, 145, 2005. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

Interestingly, the selectivity of the hydoxamic acid inhibitor of DPP IV was crucial in experiments to establish the role and existence of quiescent cell proline dipeptidase, QPP, a serine protease whose inhibition leads to the death of quiescent peripheral blood monocytes [104]. All other DPP IV inhibitors did not exhibit sufficient selectivity to discriminate between DPP IV and QPP. 

Anti-arthritic effect. Oral administration of AJA, a cannabinoid acid devoid of psychoactivity, reduced joint tissue damage in rats with adjuvant arthritis. Peripheral blood monocytes (PBM) and synovial fluid monocytes (SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AJA (0-30 mM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for messenger RNA (mRNA), and supernatants were collected for cytokine assay. Addition of AJA to PBM and SFM in vitro reduced both steady-state levels of interleukin-ly (IL-ly) mRNA and secretion of IL-ly in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 mM AJA (p < 0.05 vs untreated controls, n = 7). AJA did not influence tumor necrosis factor-a (TNF-a) gene expression in or secretion from PBM . 

Hydroquinone decreased interleukin (IL)-l secretion and protein and RNA synthesis of isolated human peripheral blood monocytes induced by Escherichia coli lipopoly-saccharide at micromolar concentrations (Carbonnelle etal., 1995). Hydroquinone (4 pmol/L) inhibited the growth of bone marrow cells from female C57BL/6 x DBA/2 mice (Seidel et al., 1991) and from male Swiss Webster and C57BL/6J mice (10 pmol/L) (Neun et al., 1992). Hydroquinone (50, 75 or 100 mg/kg bw, single intraperitoneal admi-... 

Weisberg LJ, Shin DT, Conkling PR. Identification of normal human peripheral blood monocytes and liver as sites of... 

R3. Rachmilewitz, D., Ligumsky, M., Rachmilewitz, B., Rachmilewitz, M., Tarcic, N., and Schlesinger, M., Transcobalamin II level in peripheral blood monocytes. A biochemical marker in inflammatory diseases of the bowel. Gastroenterology 78, 43-46 (1980). 

Twenty years ago, a high-affinity-binding site for uPA was demonstrated on the surface of peripheral blood monocytes and cultured cells of the human histiocytic lymphoma cell line, U937 [46]. The expression of uPAR on the cell surface of many cell types has since then been demonstrated, including a variety of neoplastic cell lines as well as nonneoplastic cells such as neutrophils, macrophages, keratinocytes, placental trophoblasts, endothelial, and smooth muscle cells [7, 33, 47-51]. The human uPAR gene has been mapped to chromosome 19ql.3 [52]. 

Finbloom, D. S., L. M. Wahl and K. D. Winestock (1991). The receptor for interferon-gamma on human peripheral blood monocytes consists of multiple distinct subunits. J Biol Chem 266(33) 22545-22548. 

Leukocyte-associated IgG egress from plasma is potentially mediated by binding of endogenous IgG or exogenously administered monoclonal antibodies to FCyRI or FCyRIII on circulating neutrophils and monocytes [2] or Fc,RIIa on platelets [24,25], Human peripheral blood monocytes also bear MHC class I-related FcRn that can transport IgG from plasma to tissue fluids, dendritic cells, or intestinal macrophages [26],... 

Y2. Yamaguchi, T., Olozak, I., Chattopadhyay, N., Butters, R. R., Kifor, O., et al., Expression of extracellular calcium (Ca2+0)-sensing receptor in human peripheral blood monocytes. Biochem. Biophys. Res. Commun. 246, 501-506 (1998). 

---