Cytokines sensitization

In most instances, ligand binding appears to promote receptor dimerization, bringing their associated JAKs into close proximity (Figure 4.2). The JAKs then phosphorylate — and hence activate — each other (transphosphorylation). The activated kinases subsequently phosphorylate specific tyrosine residues on the receptor itself. This promotes direct association between one or more members of a family of cytoplasmic proteins (STATs) and the receptor. Once docked at the receptor surface, the STATs are in turn phosphorylated (and hence activated) by the JAKs (Figure 4.2). As described below, activated STATs then translocate to the nucleus and directly regulate expression of IFN and other cytokine-sensitive genes. 

Recent studies from our laboratory additionally indicate that the transition from the monocyte to mature PAM T-suppressive phenotype is time dependent and cytokine sensitive. Following recruitment into the lung via a sterile inflammatory stimulus, murine monocytes require 5 days for full maturation (Bilyk and Holt, 1994). In addition, the presence of cytokines such as GM-CSF (especially if free TNFa is also available) inhibits the expression of suppressive activity (Fig. 1.5). If mature PAMs are cultured continuously in the presence of GM-CSF, their T cell-interactive phenotype reverts to that of... 

Treatment with specific antibodies (ALG, ATG, anti-CD3, anti-CD25) is indicated during the induction phase after transplantation and in the case of acute rejection for short time periods. Therapy with nonhuman antibodies may cause sensitization. Muromonab-CD3 might initiate a cytokine release syndrome (fever, chills, headache). 

The production of a female-influencing secretion from the chin gland of male Plethodontid salamander (P. jordani) points to a similar extension of function by the acquisition of female olfactory sensitivity to an intercellular signal protein. Female receptivity is enhanced by a male cytokine-like compound of the interleukin-6 family, in its released form. Rollman et al. (1999) note that pheromonal activity is a previously unrecognised function for cytokines. 

T cells control these learned responses and decide which tools to use in the reaction. Sometimes they choose several different tools at once, and multiple reactions ensue, such as when a person becomes sensitized to penicillin and has not only anaphylaxis but hemolytic anemia and serum sickness. There are different types of T cells, and they communicate either directly with other cells or by chemical messages called cytokines. The pattern of cytokines released is one way T cells have of determining which kind of response will occur. They are broadly called Thl andTh2 responses, with Thl mostly responding to infections and Th2 often producing allergy or asthma. 

As already mentioned, van Kuijk and colleagues (Kalariya et al., 2008) tested the effects of oxidation products of [i-carotcnc, lutein, and zeaxanthin on the activation of redox-sensitive transcription factors, NF-kB, and AP-1 in cultured ARPE-19 cells. Degradation products of all three carotenoids induced activation of NF-kB and AP-1, and these effects were ameliorated by pretreatment of cells with 1 mM NAC. NF-kB is a major transcription factor that binds to promoter sites of many pro-inflammatory cytokines such as IL-1, IL-6, TNF-a, and iNOS. These results indicate that the degradation products of carotenoids can stimulate a pro-inflammatory pathway. 

Ramegowda B, Samuel JE, Tesh VL Interaction of Shiga toxins with human brain micro-vascular endothelial cells Cytokines as sensitizing agents. J Infect Dis 1999 180 1205— 1213. 

Cytokine receptors, most notably the IL-2 receptor a subunit. (The T-lymphocytes appear to constitutively express the P and y IL-2 receptor polypeptides. Induction of the a gene leads to formation of a high-affinity apy receptor complex, thereby rendering the activated T cell highly sensitive to IL-2.)... 

TNF fails to induce death of all tumour cell types. Although many transformed cells are TNF sensitive, the cytokine exerts, at best, a cytostatic effect on others and has no effect on yet others. The cytotoxic activity is invariably enhanced by the presence of IFN-y. The concurrent presence of this interferon increases the range of transformed cell types sensitive to TNF-a, and can upgrade its cytostatic effects to cytotoxic effects. It can also render many untransformed cells, in particular epithelial and endothelial cells, susceptible to the cytotoxic effects of TNF-a. 

Hypoxia-ischemia may initiate apoptosis in parallel with excitotoxicity 565 Triggers of ischemic apoptosis may include decreased supply or sensitivity to neurotrophins, oxidative stress, exposure to inflammatory cytokines or damage to mitochondria 566... 

---