Effects on leukocyte

Recently, the activities of host defense peptides related to the resolution of infection have been suggested to result in part from nondirect antimicrobial activities. It has been postulated that immunomodulation may represent the primary action of these peptides in vivo as the immunomodulatory activities are retained under physiological conditions in contrast to the direct antimicrobial activities of most natural mammalian host defense peptides. These immunomodulatory activities include, but are not limited to, direct chemotactic activity, induction of chemokines and other immune mediators, stimulation of leukocyte degranulation and other microbicidal activities, effects on leukocyte and epithelial cell survival and apoptosis, stimulation of epithelial and endothelial cell proliferation, promotion of wound healing and angiogenesis, antiendotoxic and anti-inflammatory activities, and adjuvant fiinctions. These will be described in detail in the following sections and a summary is found in Table 1. 

Lipoxins have diverse effects on leukocytes, including activation of monocytes and macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin inhibit natural killer cell cytotoxicity. 

In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene, and platelet-activating factor synthesis that results from activation of phospholipase - Finally, glucocorticoids reduce expression... 

Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobacter pylori. They also promote fat redistribution in the body, with increase of visceral, facial, nuchal, and supraclavicular fat, and they appear to antagonize the effect of vitamin D on calcium absorption. The glucocorticoids also have important effects on the hematopoietic system. In addition to their effects on leukocytes, they increase the number of platelets and red blood cells. 

It has recently been established that bacterial DNA, but not vertebrate DNA, has direct immunostimulatory effects on leukocytes in vitro. The immunostimulatory effect is due to unmethylated CpG dinucleotides, which are underrepresented and methylated in vertebrate DNA. CpG DNA and synthetic oligonucleotides from a variety of sources have shown significant promise as new adjuvants (10-12). CpG induces a strong Thl response, mainly by stimulating cytokine induction and through the expression of costimulatory molecules on antigen-presenting cells. CpG is currently in clinical trials and may become part of a licensed product in the future. 

Nitrobenzofurazans have been observed as powerful inhibitors of nucleic acid biosynthesis, with an especially toxic effect on leukocyte metabolism in vitro. These compounds exhibit an extremely high electrophilic reactivity as reflected judging by their ability to form Meisenheimer c-complexes, investigated in detail in [761-773],... 

More animal than human data are available from which to determine LOAEL or NOAEL values of benzene hematotoxicity. The data show that animal responses to benzene exposure are variable and may depend on factors such as species, strain, duration of exposure, and whether exposure is intermittent or continuous. Wide variations have also been observed in normal hematological parameters, complicating statistical evaluation. The studies show that benzene exerts toxic effects at all phases of the hematological system, from stem cell depression in the bone marrow, to pancytopenia, to histopathological changes in the bone marrow. The following studies demonstrate these adverse hematological effects in animals. Effects on leukocytes, lymphocytes, and bone marrow are also discussed in Section 2.2.1.3. 

Bromelain is a mixture of cysteine proteases obtained from pineapple stems (Ananas comosus, Bromeliaceae) that has been used therapeutically for the treatment of inflammation and trauma [119]. 7n vitro, it has varied stimulatory effects on leukocyte populations, increases CD2-mediated T cell activation, enhances Ag-independent binding to monocytes, etc. The effects of bromelain have previously been attributed to its degradative action at cell surfaces. However, it also acts independent of the removal of cell surface molecules [120]. In order to investigate the possible hormonelike effects of bromelain on intracellular signalling, its effects on TCR7CD3 signalling and IL-2 production were studied. It was observed that bromelain inhibits ERK-2 activation in ThO cells stimulated via the TCR, or with combined TPA plus calcium ionophore. In addtion, bromelain decreased IL-2, IFN-y, and IL-4 mRNA accumulation in ThO cells stimulated with TPA plus calcium ionophore, while the cytokine mRNA accumulation in cells stimulated via TCR was not affected. It seems that bromelain does not act on ERK-2 directly but also inhibits p2r activation, an effector molecule upstream from ERK-2 in the Raf-1/MEKl/ERK kinase cascade. Since p21 is an effector for multiple MAPK pathways, it is likely that bromelain affects other MAPK signalling cascades, such as the INK pathway or p38 MAPK pathway [121],... 

Human leukocytes possess alkaline phosphatase (L13, 03, RIO, T6, V3, V4) whose activity parallels the concentration of certain circulating steroids. Thus, during the menstrual cycle, the leukocyte alkaline phosphatase evidences a peak at midcycle corresponding to the higher estrogen level. In the later stages of pregnancy the enzyme level increases. Corti-coid hormones also exert an effect on leukocyte alkaline phosphatase. 

This effect on leukocyte adhesion obtained with rhAT is similar to the activity of hpAT observed in related models. For example, in the skinfold of endotoxemic Syrian hamster, multiple injections of 250 U kg of hpAT attenuated LPS-in-duced arteriolar and venular leukocyte adhesion [92, 93]. Here again, this effect was completely abolished by pretreatment with indomethacin. Previously, in a feline me-... 

The pharmacodynamics properties of the propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin) do not differ significantly. All are nonselective cyclooxygenase inhibitors with the effects and side effects common to other tNSAlDs. Although there is considerable variation in their potency as COX inhibitors, this is not of obvious clinical consequence. Some of the propionic acid derivatives, particularly naproxen, have prominent inhibitory effects on leukocyte... 

De Vos C HI -receptor antagonists Effects on leukocytes, myth or reality [reviewl Clin Exp Allergy 29... 

Endocannabinoid Effect on Leukocyte and Lymphocyte Functional Responses.439... 

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