Local cytokines

The earliest morphological change in the sebaceous follicle is an abnormal follicular epithelial differentiation, which results in ductal hypercornification. Cornified cells in the upper section of the follicular canal become abnormally adherent. Comedones represent the retention of hyperproliferating ductal keratinoc-ytes in the duct. Several factors have been implicated in the induction of hyperproliferation sebaceous lipid composition, androgens, local cytokine production (IL-i, EGF) and bacteria (P. acnes). 

Therapeutic irradiation is known to have multiple interactions with the vasculature of the irradiated tissue (12). Radiation has direct cytotoxic effects on the vascular endothelium, likely due to induction of oxidative injury. Radiation-induced injury stimulates inflammation and influx of inflammatory cells in addition to creating aprocoagulant state in the vascular space by the transcriptional induction of tissue factor with the subsequent activation of coagulation factors as well as von Willebrand factor and platelets. Experimental evidence suggests that the mechanism by which radiation initiates these responses is in part through the induction of cell-adhesion molecules including ICAM-1, E-selectin, and P-selectin and in part through local cytokine production and release (13). 

The pool of upstream systemic IL-1, IL-6, TNF-a and IgG, IgM, including autoantibodies is bigger than the pool of local down-stream ones in early disease. In late disease the pool of local cytokines, TNF-a, and autoantibodies is bigger than the pool of the upstream ones. This happens when symmetrical poly-arthritis, trigger points of enthesitis, and secondary fibromyalgia have developed. That is why weekly PA is as important as IVT in late stages of the disease. 

Osteoclasts are multinucleated cells found on the endosteal surface of bone, in Haversian systems and periosteal surfaces. PTH activates osteoclasts (indirectly via osteoblasts that possess PTH receptors). Calcitonin is a potent inhibitor of osteoclast activity. Local cytokine factors, including interleukin-1 (IL-1), tumour-necrosis factor (TNF), TGF- 0 and interferon-y (INF-y), are important regulators. Osteoclast resorption of bone releases collagen peptides, pyridinoline cross-links and calcium from the bone matrix, through the action of lysosomal enzymes (collagenases and cathepsins). The collagen breakdown products in serum and urine (e.g. hydroxyproline) can be used as biochemical markers. 

In summary, it is clear that cytokines play a critical role in the regulation of both the amount and the class of immunoglobulins secreted by B lymphocytes at mucosal surfoces. Conversely, B lymphocytes themselves may influence local cytokine synthesis by T lymphocytes, as exemplified by their differential capacity to present soluble antigens to ThI and Th2 T lymphocytes (described previously). 

Kadota and his associates [15] demonstrated an increase of neutrophil chemo-tactic activity (NCA) in BALE, which showed a clear correlation with neutrophil numbers. They further showed that inflammatory cytokines such as IL-8, IL-lp, and TNF-a were also increased in BALE from patients with chronic airway inflammatory diseases such as DPB and bronchiectasis [25]. They showed that treatment with 14-membered ring macrolide antibiotics such as EM caused a decline in both neutrophil number and these inflammatory cytokines and chemo-kines. These cytokines are potent activators of neutrophils, among which IL-8 is one of the most potent chemotactic factors in the airways [55, 56]. Therefore, it is probable that EM attenuates airway inflammatory responses by decreasing the local cytokine/chemokine levels and thus decreasing the recruitment of inflammatory cells such as neutrophils. 

The second general strategy for local cytokine delivery involves direct loading onto polymers. In 1998, Wiranowska et al. established, as proof of principle, that polymers were capable of the sustained release of biologically active cytokines (116). Both in vitro and in vivo experiments documented the release of active murine IFN-a/j8 by loaded EVAc polymers. In vitro assays determined the majority of activity release occurred in the first 4 days in vivo trials suggested most of activity release spanned the first 24 h with gradual tapering over the next 3 days. 

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