Antiinflammatory cytokines

Compensatory physiologic response to systemic inflammatory response syndrome that is considered secondary to the actions of antiinflammatory cytokine mediators. 

Elenkov, I J. and Chrousos, G.P., Stress hormones, Thl/Th2 patterns, pro/antiinflammatory cytokines and susceptibility to disease, Trends Endocrinol. Metab., 10, 359, 1999. 

Lattmann T, Hein M, HOrber S, Ortmann J, et al. 2005. Activation of pro-inflammatory and antiinflammatory cytokines in host organs during chronic allograft rejection Role of endothelin receptor signaling. Am J Transplant. 5 1042-1049. 

Th2 cytokine IL-10 is an antiinflammatory cytokine that suppresses the secretion of proinflammatory cytokines (Dll), allergen-induced airway inflammation, and nonspecific airway responsiveness (T9). IL-13 shares a receptor component, signaling pathways, and many biological activities with IL-4. In fact, IL-13 is also an antiinflammatory cytokine and plays a unique role in the optimal induction and maintenance of IgE production and IgE-mediated allergic responses when IL-4 production is low or absent (DIO, W12). Moreover, IL-13 or IL-4 shows a synergistic effect with TNF-a or IL-5 on eosinophil activation (L20). Recently, IL-11 was found to be involved in the chronic remodeling seen in asthmatic airways and is associated with increasing severity of the disease (Ml6). 

Okamoto, K., Martin, D. P., Schmelzer, J. D., Mitsui, Y., and Low, P. A. (2001). Pro- and antiinflammatory cytokine gene expression in rat sciatic nerve chronic constriction injury model of neuropathic pain. Exp. Neurol 169, 386-391. 

Based on experimental and clinical data, cerebral hypothermia appears to be a potent therapeutic approach to treating brain trauma. However, recent results from the Multicenter National Brain Injury Study Hypothermia (NABIS H) clinical trial appear to be disappointing, and more refinement of the clinical application of hypothermia is required (73). Additional clinical trials are now required to evaluate systematically the beneficial effects of clinical hypothermia in different populations of brain-injured patients. In addition, experimental data regarding the beneficial effects of combination therapy are required to evaluate whether hypothermia plus pharmacotherapy may provide a better outcome. Forexample, mildpostischemichypothermia(33-39°C) combined with the antiinflammatory cytokine IL-10 has recently been reported to produce long-term protection of the C Al hippocampus after transient global ischemia (74). Hypothermia or IL-10 treatment alone did not protect chronically. In contrast, Kline etal. (75) showed that acute systemic administration of IL-10 suppressed the beneficial effects of... 

The pathogenesis of inflammatory bowel disease is still poorly understood. Immune mechanisms are probably involved, and potential antigens include intestinal bacteria and intestinal epithelium. Abnormalities in inflammatory mediators have also been described it has been suggested that an imbalance between proinflammatory and antiinflammatory cytokines may determine susceptibility, although the abnormalities observed could simply be secondary to the disease process. 

One such phenomenon is endotoxin tolerance. It is known that LPS stimulation is associated with a prompt response (NF-/cB translocation to the nucleus and cytokine production) followed by a refractory state, wherein a second challenge is far less effective at provoking such a response (97,98). Cross-tolerance has been observed when a primary stimulus with lipopeptides is used in place of LPS (99). Although some have attributed tolerance to the production of antiinflammatory cytokines such as TGF/3 and/or IL-10 (100), it is more widely held that tolerance reflects the activation of a feedback pathway within cells, causing paralysis of the LPS response. One example of tolerance at the cellular level involves the production of NF-kB p50 homodimers, which can bind to diverse promoters within the cell and prevent activation by p50/p65 heterodimers (101). Other levels of blockade are also possible and are currently under investigation. 

Elamilton TA, Ohmori Y, Tebo JM, Kishore R. 1999. Regulation of macrophage gene expression by pro- and antiinflammatory cytokines. Pathobiology 67 ... 

Zhang Q, Wan R, Mo Y, Wang J, Chien S (2008) Intracellular ATP delivery accelerates skind wound healing through pro- and antiinflammatory cytokine expressions (Abstract). Wound Repair Regen 16 A57... 

Cliriical trials involving antiinflammatory cytokines or cytoldne inhibitors (anticytokines, monoclonal antibodies, and soluble receptors) require the monitoring of cytokines during the course of these treatments. 

Gingivitis is Reversible Antiinflammatory Cytokines Mediate Repair... 

Van der Poll T, Malefyt RW, Coyle SM, Lowry SF. Antiinflammatory cytokine responses during chnical sepsis and experimental endotoxemia Sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, IL-13. J Infect Dis 1997 175 118-122. 

Figure 10.3 Major effects of l,25(OH)2D3 at the T cell synapse involve reduced antigen presentation, reduced intercellular adhesion, reduced costimulatory activity, reduced secretion of proinflammatory cytokines and increased secretion of antiinflammatory cytokines leading to reduced T cell and B cell activation.

Data are also available for MS patients, where supplementation with 25(OH)2D3 increased serum levels of antiinflammatory cytokine TGF-J3 after 6 months of treatment, whereas no or little effect was observed on TNF-a, IL-13, IFN-y and IL-2 [187]. No information was given on the clinical presentation of these patients after treatment. In type I diabetes, a long-term study proved dietary vitamin D supplementation was clinically beneficial in terms of reduced risk of the disease [165]. Heart transplant recipients that were treated with low-dose l,25(OH)2D3 aiming at reduction of bone loss required significantly less cyclosporin for prevention of organ rejection suggesting a potentially beneficial immunosuppressive role of l,25(OH)2D3 in transplantational medicine [188]. 

These data support the view that inhibition of iNOS induction by antiinflammatory cytokines can be achieved in vitro as well as in vivo. The action of these cytokines may importantly contribute to their protective effect in various models of septic shock. For example, it is known that IL-10 protects in rodent models of septic shock, whereas neutralization of endogenous IL-10 has deleterious consequences (Gerard etal., 1993 Marchantet t/., 1994). 

There is an accumulating amount of evidence supporting the hypothesis that the induction of iNOS by endotoxin in vivo is secondary to the release of cytokines and other humoral mediators, including TNF, IL-1, and PAF (see above). For example, pretreatment of rats with monoclonal antibodies to TNF, with endogenous IL-l,a, or with PAF antagonists attenuates the delayed circulatory failure (hypotension and vascular hyporeactivity to vasoconstrictor agents) as well as the induction of iNOS in the lung. Similarly, inhibition of iNOS induction can be achieved by pretreatment with antiinflammatory cytokines, such as IL-4 or IL-10. Certain polyamines, such as spermine, are potent inhibitors of iNOS induction in vitro. However, no data are available as to whether polyamines are able to inhibit the induction of iNOS in vivo. 

The last point highlights an interesting feature of the control architecture of the macrophage transcriptional network. We have reviewed elsewhere the observation that many of the most LPS-inducible transcripts are actually not effectors of immunity, but feedback controllers that act at every level of the signalling pathway from the receptor to transcription, as well as repressors of the effectors (such as protease inhibitors and antiinflammatory cytokines) (Wells et al 2005). One might consider that this multilevel control exists to ensure robustness, but in fact mutation in any individual control leads to disordered or excessive macrophage activation. A prediction of the observation that the feedback control is itself inducible, and the system is sensitive to that feedback control, is that it will be relatively insensitive to inhibitors that act on the afferent pathways (Wells et al 2005). 

Terrazas LI, Walsh K, Piskorska D, McGuire E, Harn DA. The schistosome oligosaccharide lacto-N-neotetraose expands Grl(+) cells that secrete antiinflammatory cytokines and inhibit proliferation of naive CD4(+) cells a potential mechanism for immune polarization in helminth infections. J Immunol 2001 167 5294-5303. 

Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest I998 101 3II. 

IL-10 is a potent antiinflammatory cytokine that shares with adenosine the ability to control TNF release after LPS challenge (de Waal Malefyt et al. 1991, GfiRARD et al. 1993, Marchant et al. 1994). 

FBGC formation is considered the hallmark of the foreign body reaction and is orchestrated by a combination of pro- and antiinflammatory cytokines [20]. The totality of the foreign body reaction, which takes several weeks, involves the activation of proinflammatory, traditionally activated macrophages (Ml) and alternatively activated M2 macrophages, which are involved in tissue remodeling [21]. 

The therapeutic effect of ECP for GVHD appears to involve induction of apoptosis in psoralen plus UVA-exposed lymphocytes, modulation of monoc3de-derived dendritic cell differentiation, increased production of antiinflammatory cytokines, decreased dendritic cell antigen-presenting function, and induction of regulatory T cells that establish immune tolerance [200,201]. 

---