Cytokine production inhibitory effect

IFN-y also directly modulates the immune response by affecting growth, differentiation and function of both T- and B-lymphocytes. These effects are quite complex and are often influenced by additional cytokines. IFN-y acts as a growth factor in an autocrine manner for some T cell sub-populations, and it is capable of suppressing growth of other T cell types. It appears to have an inhibitory effect on development of immature B-lymphocyte populations, but it may support mature B cell survival. It can both up-regulate and down-regulate antibody production under various circumstances. 

If jS-cell production of nitric oxide participates in IDDM, human islets must produce nitric oxide in response to cytokines. We have shown that a combination of cytokines (lL-1, IFN, and TNF) induce the formation of nitric oxide by isolated human islets (Corbett et al., 1993b). The formation of nitric oxide has been demonstrated by cytokine-induced cGMP accumulation, nitrite formation, and EPR-detectable iron-nitrosyl complex formation (Fig. 12), all of which were prevented by NMMA. The cytokine combination of IFN and lL-1 are required for nitrite production, while TTSIF potentiates IL-1 and IFN-induced nitrite formation by human islets. The cytokine combination of lL-1, TNF, and IFN also influences the physiological function of insulin secretion by human islets. Low concentrations of this cytokine combination slightly stimulate insulin secretion, while high concentrations inhibit insulin secretion, similar to the concentration-dependent effects of lL-1 on rat islet function. NMMA partially prevents the inhibitory effects of this cytokine combination on insulin secretion from human islets, suggesting that nitric oxide may participate in )3-cell dysfunction associated with IDDM. 

IL-22. IL-10-related T cell-derived inducible factor (IL-TIF provisionally designated IL-22) is a cytokine distantly related to IL-10 and is produced by activated T cells (D16). IL-22 receptor, a new member of the interferon receptor family, and CRF2-4, a member of the class II cytokine receptor family, join together to enable IL-22 signaling. Cell lines that respond to IL-22 by activation of STATs 1,3, and 5, but unresponsive to IL-10, have been identified (XI). In contrast to IL-10, IL-22 does not inhibit the LPS-induced production of proinflammatory cytokines by monocytes, but it has a modest inhibitory effect on IL-4 production from Th2 cells (XI). 

The direct effects opioid and opioidlike peptides exhibit on cells of the immune system is both varied and, in some instances, contradictory, depending on which receptor subtype is being studied. Mu and kappa receptors generally affect immunofunction in a suppressive manner, where delta receptors tend to express immunostimulation [82-85]. However, selected delta antagonists have shown to elicit suppressive effects on B-cell proliferation, NK cell activity, and T-helper cell cytokine production [86]. The alteration of leukocyte function via opioid receptors will be discussed highlighting specific cell subtype immunomodulation. Endorphin shows a inhibitory effect on splenocyte proliferation through central and peripheral autocrine/paracrine pathways [87]. 

Conneely, 2001). LF has the ability to bind to the surface of several types of immune cells, which suggests that it can modulate immune functions. Both stimulatory and inhibitory effects of LF on lymphocyte proliferation have been described in the literature. LF has been reported to induce in vitro maturation of T- and B-lymphocytes, to modulate the activity of natural killer cells and to enhance the phagocytic activity of neutrophils. In mice, bovine LF has been shown to induce both mucosal and systemic immune responses (Debbabi et al., 1998). Cell-culture studies have demonstrated that LF and peptides derived from LF influence the production of various cytokines which regulate the immune and inflammatory responses of the body (Crouch et al., 1992 Shinoda et al., 1996). 

Cytokines modify phagocyte activity and may interfere with the immunomodulating properties of antibacterial agents. In an in vitro study, TNF-a and GM-CSF reduced the inhibitory effect of telithromycin on oxidant production by polymorphonuclear neutrophils, suggesting an effect of telithromycin downstream of the priming effect of cytokines. In addition, TNF-a and GM-CSF moderately impaired the uptake of telithromycin by polymorphonuclear neutrophils the inhibitory effect of these two cytokines seemed to be related to the activation of the p38 mitogen-activated protein kinase (12). 

Berdyshev et al. (1997) examined the effects of anandamide, palmitoylethanolamide and THC on the production of TNF-a, IL-4, IL-6, IL-8, IL-10, IFN-y, p55, and p75 TNF-a soluble receptors expressed by stimulated human peripheral blood mononuclear cells as well as [ H]-arachidonic acid release by non-stimulated and N-formyl-Met-Leu-Phe (fMLP)-stimulalcd human monocytes. Anandamide diminished IL-6 and IL-8 production at low nanomolar concentrations and inhibited the production of TNF-a, IFN-y, IL-4, and p75 TNF-a soluble receptors at higher concentrations (i.e., micromolar levels). Palmitoylethanolamide inhibited IL-4, IL-6, and IL-8 synthesis and the production of p75 TNF-a soluble receptors at concentrations similar to those of anandamide but did not affect TNF-a and IFN-y production. Neither anandamide nor palmitoylethanolamide influenced IL-10 synthesis. THC, on the other hand, exerted a biphasic effect on pro-inflammatory cytokine production. TNF-a, IL-6, and IL-8 synthesis was inhibited maximally by 3 nM THC but stimulated by 3 pM THC. A similar effect was observed for IL-8 and IFN-y. The level of IL-4, IL-10, and p75 TNF-a soluble receptors was diminished by 3 pM THC. [ H]-Arachidonate release was stimulated only by high THC and anandamide concentrations. Based on these observations, the investigators suggested that the inhibitory properties of anandamide, palmitoylethanolamide, and THC are determined by the activation of peripheral-type cannabinoid receptors (i.e., CB2) and that various endogenous fatty acid ethanolamides also participate in the regulation of the immune response. 

Topical tacrolimus suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during the initial skin immune response [97]. The inhibitojy effect of tacrolimus on the production of cytokines in T cells has been demonstrated in both Thl and Th2 cells [98]. This is coincident with reports that the transcription factor NEAT, a target for the calcium-regulated phosphatase calcineurin, mediates transcription of both Thl- and Th2-derived cytokines [99]. The effects of tacrolimus on other inflammatory cells such as skin mast cells, basophils, eosinophils, and Langerhans cells have also been studied extensively. Tacrolimus has been shown to inhibit histamine release and cytokine production from human skin, lung, and cord blood-derived cultured mast cells [100-102]. Tacrolimus has also been reported to have a direct inhibitory activity on eosinophil activation [103,104]. 

EM also has a motilin-like stimulating activity on gastrointestinal smooth muscles [39]. Therefore, the inhibitory effect on cytokine expression in human cells summarized here may be a third bioactivity of the macrolide antibiotic. We recently reported that some of these derivatives have inhibitory effect on IL-8 production by human airway epithelial cells [72], These analogues also showed inhibitory action on the activation of NFkB and AP-1 assessed by EMSA (M. Desaki etal., unpublished observations, January 2001). Characterization of the chemical structure responsible for its potential would be important to pursue and further investigation for the molecular mechanism would be necessary for a possible new type of anti-inflammatory agent. 

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