The interleukin-5 (IL-5)-IL-5-receptor system has been of great interest because the IL-5-receptor (IL-5R) contains the common cytokine-receptor β-chain (βc), which is shared with the GM-CSF receptor and IL-3 receptor. IL-5 is produced by type 2 T helper cells (Th2), mast cells, and eosinophils, and non-hematopoietic cells. As we discuss, IL-5 has pleiotropic actions, from enhancing the homeostatic proliferation and survival of B-1 cells through noncognate stimulation and driving the differentiation of B-1 and B-2 cells into terminally differentiated plasma cells to augmenting the survival and activation of eosinophils. Thus, IL-5 links natural and adaptive immunity specific to the epitopes of natural ligands and exogenous antigens leading to the inducion of Ig-producing cells, regulating chronic inflammation and controlling disease. The potential roles of IL-5 in immune responses, allergy and autoimmunity make it attractive candidate for use in the clinical setting.

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Crohn's disease (CD) and Ulcerative colitis (UC) comprise a series of inflammatory bowel disease (IBD) resulting from chronic up-regulation of the mucosal immune system. Although the pathogenesis of IBD remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals, which are directed by genetic factors, immunological factors, and environmental factors such as foods and enteric microbes. Regarding genetic factors, important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for CD. New data on CARD15/NOD2 function and nuclear factor-κB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional “innate” pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The “germ concept” and the “genetic concept” of IBD pathophysiology are converging. The evidence continues to accumulate that CD is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarization. T-cell resistance to apoptosis occurs in CD, and human and mouse studies indicate that the signaling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Progress in understanding the pathophysiology of UC remains slow, but IL-13 produced by natural killer T cells may be involved. There is a possibility that UC might be a sort of syndrome such as viral/bacterial infectious diseases and autoimmune disorders. Despite the evidence of a role for Th1 in CD, support for a Th2 pathogenesis in ulcerative colitis is much weaker. The presence of autoantibodies, such as anticolon antibody, antimucin antibody, or antitropomyosin antibody, is suggestive of a Th2 pathogenesis. There are several conflicting immunological findings, but some immunological abnormalities may induce colonic inflammation.

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Grepafloxacin is an asymmetric fluoroquinolone derivative, which possesses high tissue penetrability as well as strong, broad-spectrum antimicrobial activities. Human neutrophils actively internalize fluoroquinolones, especially grepafloxacin, and grepafloxacin induces a priming effect on neutrophil respiratory burst produced by fMLP. However the precise mechanism of the uptake and the priming effect are not fully understood. We show here that mitogen activated protein kinase (MAPK) plays a role in the uptake and in the priming effect in neutrophils. Our results strongly suggest that grepafloxacin negatively regulates its uptake in neutrophils, and p38 MAPK activation is involved in this down-regulation of grepafloxacin uptake. The ciprofloxacin uptake is positively regulated by the activation of PKC, and p44/42 MAPK activation is involved in this up-regulation. Neither PKC, nor p38 or p44/42 MAPK is involved in the regulation of ofloxacin uptake. Grepafloxacin stereospecifically primes neutrophil respiratory burst. Stereospecific phosphorylation of p38MAPK, and translocation of p47 and p67 phox proteins are closely related to grepafloxacin priming.

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Clostridium difficile (C. difficile) is a major causative agent of antibiotics-associated diarrhea and pseudomembranous colitis in humans. Pathogenic strains of C. difficile release toxin A, which is referred as enterotoxin due to its capacity to disrupt intestinal epithelial structure. Toxin A causes tissue damages directly by glucosylation of Rho and indirectly by inducing massive infiltration of neutrophils. We previously observed that interferon (IFN)-γ-deficient mice exhibited less neutrophil infiltration and tissue damages in several types of acute inflammation in liver. These observations prompted us to explore the roles of IFN-γ in toxin A-induced acute enteritis model. Injection of toxin A into ileal loops caused massive fluid secretion, disruption of epithelial structure, and massive neutrophil infiltration in wild-type (WT) mice, accompanied with increases in IFN-γ mRNA expression and protein contents in the intestine. A double-color immunofluorescence analysis detected IFN-γ protein in infiltrating neutrophils and to a lesser degree, CD3-positive lymphocytes. On the contrary, toxin A failed to induce fluid secretion, disruption of intestinal epithelial structure, and neutrophil infiltration in IFN-γ-deficient mice. Similarly, pretreatment of neutralizing anti-IFN-γ antibody prevented toxin A-induced enteritis. These observations suggest that IFN-γ is a good molecular target for the control of C. difficile-associated pseudomembranous colitis.

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TA-270 is a novel compound that demonstrates 5-lipoxygenase (LO) inhibition and anti-oxidative action against ONOO^- etc. TA-270 was designed on the basis of the ascorbic acid and aspirin, and added with sinapinic acid (an active ingredient of SAIBOKUTOU). Here, we investigated the effects of TA-270 on inflammatory airway diseases using experimental guinea pig models.
In a pre-clinical study, TA-270 strongly improved biphasic asthmatic responses and hyperresponsiveness in allergic asthma models, hyperresponsiveness induced by ozone inhalation in non-allergic models and also biphasic nasal blockages in allergic rhinitis models. The inhibitory effect of TA-270 against the hyperresponsiveness in allergic models was remarkably stronger than that of a cysteinyl leukotriene antagonist, suggesting that the anti-oxidative action rather than 5-LO inhibitory effect contributes to the inhibitory effect of TA-270. It is recently reported that a potent oxidant ONOO^- generated from nitric oxide and O₂^- is involved in the development of respiratory diseases. And our study showed that TA-270 inhibited hyperresponsiveness induced by ONOO^- in guinea pigs. These results suggest that the anti-oxidative action of TA-270 is involved in the improvement of airway inflammation.
In conclusion, TA-270 is considered to improve airway inflammation through its mechanism of 5-LO inhibitory and anti-oxidative effect, and is expected clinically to demonstrate improvement in airway inflammation including asthma and chronic obstructive pulmonary disease, and allergic rhinitis.

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Vioxx (rofecoxib) was withdrawn from the market because of a higher rate of cardiovascular events. An increased risk of cardiovascular events has also been reported with valdecoxib in patients with coronary artery bypass grafting and in a recent colon cancer trial of high-dose celecoxib.
The reason for the propensity of COX-2 inhibitors to facilitate cardiovascular events remains unclear. One possible mechanism is an imbalance between prostacyclin (PGI₂, antithrombotic) and thromboxane (TXA₂, prothrombotic) since PGI₂ production mainly depends on COX-2 activity. However, recent reports demonstrated that low-dose aspirin did not mitigate cardiovascular risk associated with COX-2 inhibitors. Co-administration of aspirin with a COX-2 inhibitor may restore the balance between PGI₂ and TXA₂ because low-dose aspirin selectively inhibits TXA₂ production in platelets. Thus, the failure of low-dose aspirin to attenuate the cardiovascular risk associated with COX-2 inhibitors implies that the COX-2 inhibitor increases the risk of cardiovascular events, at least in part, by mechanisms unrelated to TXA₂ production.
The heart has a remarkable ability to adapt to various stresses, such as ischemia, hypoxia, and oxidative stress. This is exemplified by ischemic preconditioning (IPC), the phenomenon whereby a sublethal ischemic stress greatly enhances the tolerance of the myocardium to subsequent ischemia. The occurrence of IPC has been shown in almost all mammalian tissues and has also been confirmed in humans, where it may play an important role in protecting the heart from coronary artery disease. We demonstrated that induction of COX-2 plays an obligatory role in the development of IPC, most likely via the production of cardioprotective prostanoids such PGI₂ and PGE₂. Since then, mounting evidence has accumulated which supports the concept that COX-2 is a cardioprotective protein that alleviates myocardial ischemia/reperfusion injury. We have suggested that induction of COX-2 is a fundamental mechanism whereby the heart adapts to stress. Importantly, low-dose aspirin does not interfere either with COX-2 or with IPC.
We propose another mechanism for the detrimental effects of COX-2 inhibitors, namely, that, in addition to their prothrombotic actions, these drugs may deprive the heart of its natural ability to adapt to ischemic stress (i.e., IPC), thereby increasing the susceptibility of the myocardium to infarction and stunning. We suggest that the biological effects of COX-2 may differ depending on the degree of its expression, cellular types where it is expressed (e.g., infiltrating cells vs. cardiac myocytes), and the ability of cells to metabolize COX-2-derived PGH₂ into cytoprotective prostanoids.

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Human neutrophils undergo spontaneous apoptosis, and spontaneous neutrophil apoptosis is delayed in the presence of various inflammatory cytokines, including G-CSF, GM-CSF, IFN-α and IFN-γ. These cytokines exert the antiapoptotic effect on human neutrophils in a protein-synthesis dependent mechanism, indicating that certain antiapoptotic molecules are up-regulated by stimulation with these cytokines. Human neutrophils express Bcl-2 family (Mcl-1, A1 and Bcl-X_L) and IAP (inhibitor of apoptosis) family (cIAP1, cIAP2, XIAP and survivin) members, both of which may be involved in cytokine-mediated anti-apoptotic effect. Among these molecules, cIAP2 is found to be selectively up-regulated by stimulation with G-CSF, IFN-α and IFN-γ via activation of the JAK2/STAT3 pathway, and overexpression of cIAP2 is detected in a patient with chronic neutrophilic leukemia.

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