Venkatesh Ponemone

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice.

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.

Suppressed cytokine production in whole blood cultures may be related to iron status and hepcidin and is partially corrected following weight reduction in morbidly obese pre-menopausal women

OBJECTIVE Assess ex vivo whole-blood (WB) cytokine production and its association with iron status and serum hepcidin in obese versus non-obese women. Determine the change in ex vivo WB cytokine production 6 months after restrictive bariatric surgery in the obese group. SUBJECTS Seventeen obese (BMI: 46.6±7.9 kg/m²) and 19 non-obese (BMI: 22.5±3.0 kg/m²), pre-menopausal women; frequency matched for hemoglobin, age and race. MEASUREMENTS At baseline control and ex vivo stimulated IL-6, IL-10, IL-22, IFNγ, and TNFα from heparinized WB cultures, hemoglobin from finger-stick and transferrin receptor, hepcidin, CRP, IL-6, HOMA-IR from fasted serum samples and anthropometric parameters were assessed in the women. All parameters were reassessed 6-months following restrictive bariatric surgery in the obese women only. RESULTS Whole blood ex vivo LPS and ZY stimulated production of IL-6, TNFα, and IFNγ was reduced, IL-22 increased, and IL-10 was unaffected in obese compared with the non-obese women. Furthermore, ex vivo stimulated production of IL-6 and TNFα normalized, but IFNγ production remained unchanged with weight loss following restrictive bariatric surgery. In the obese women, serum transferrin receptor (a marker of iron status) and serum hepcidin were correlated with ex vivo stimulated IFNγ production at baseline. CONCLUSION Ex vivo LPS and ZY stimulated cytokine production from WB cultures was altered in pre-menopausal women with morbid obesity. Significant weight loss resulted in normalization of some but not all observed alterations. Furthermore, iron status and serum hepcidin were associated with ex vivo LPS and ZY stimulated IFNγ in obesity.

Apoptosis and Inflammation: Role of Adipokines in Inflammatory Bowel Disease

OBJECTIVES:Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohns disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD.METHODS:Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied.RESULTS:Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN.CONCLUSION:Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.

The role of adipose tissue-associated macrophages and T lymphocytes in the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract that affect more than 3 million people worldwide, but the pathological etiology is still unknown. The overall purpose of our investigations was to elucidate the possibility of pathological causes of IBD, and therefore, we determined the difference of inflammatory cytokine profiles in adipose tissue macrophages (ATMs) and T lymphocytes (ATTs) obtained near active lesions of IBD; investigated whether the alteration in ATM activation induces genes involved in collagen formation; and evaluated the effects of fatty acid oxidation inhibitors on factors involved in inflammation and collagen production by ATMs in IBD. Adipose tissues (ATs) were collected near active lesions and also at the margin of resected segments of the bowel from IBD patients with ulcerative colitis (UC) and CD (n=14/group). Normal appearing ATs from control subjects (n=14) who had colon resection for adenocarcinoma were collected as far away from the cancer lesion as possible to rule out possible changes. Compared with inactive disease lesions, ATMs and ATTs from active lesions released more IL-6, IL-4 and IL-13. Treatments of cytokine IL-4 and/or IL-13 to ATMs reduced iNOS expression but increased Arg-I expression which were exacerbated when treated with T cell- and adipocyte-conditioned medium. However, fatty acid oxidation inhibitors prevented the effects of cytokines IL-4 and/or IL-13 on iNOS and Arg-I expressions. This study was the first to show the effect of IL-4 and IL-13 on collagen formation, through iNOS and Arg-I expressions, that was exacerbated in a condition that mimics in vivo condition of active lesions. Moreover, our study was the first to provide potential benefits of fatty acid oxidation inhibitors to ATMs on preventing collagen formation; thus, providing therapeutic implications for individuals with intestinal fibrosis and stricture lesions, although future study should be guaranteed to elucidate the underlying mechanisms.

Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation.

Adiponectin (APN) is an adipose tissue-derived cytokine that regulates insulin sensitivity and inflammation. It is also involved in modulation of cell proliferation by binding to various growth factors. Based on its known effects in modulating cell proliferation and oxidative stress, APN may potentially be involved in regulating tissue damage and repair following irradiation. Adiponectin KO mice and their WT littermates were exposed to a single whole-body dose of 3 or 6Gy gamma radiation. Radiation-induced alterations were studied in jejunum, blood, bone marrow and thymus at days 1 and 5 post-irradiation and compared with sham-irradiated groups. In WT mice, irradiation did not significantly alter serum APN levels while inducing a significant decrease in serum leptin. Irradiation caused a significant reduction in thymocyte cellularity, with concomitant decrease in CD4(+), CD8(+) and CD4(+)CD8(+) T cell populations, with no significant differences between WT and APN KO mice. Irradiation resulted in a significantly higher increase in the frequency of micronucleated reticulocytes in the blood of APN KO compared with WT mice, whereas frequency of micronucleated normochromatic erythrocytes in the bone marrow at day 5 was significantly higher in WT compared with APN KO mice. Finally, irradiation induced similar alterations in villus height and crypt cell proliferation in the jejunum of WT and APN KO mice. Jejunum explants from sham-irradiated APN KO mice produced higher levels of IL-6 compared with tissue from WT animals, but the difference was no longer apparent following irradiation. Our data indicate that APN deficiency does not play a significant role in modulating radiation-induced gastrointestinal injury in mice, while it may participate in regulation of damage to the hematopoietic system.

Medicinal Benefits of Ginger in Various Gastrointestinal Ailments: Use in Geriatric Conditions

Ginger, the rhizome of Zingiber officinale Roscoe (family Zingiberaceae), is not only a food condiment but also a medicinal agent with numerous medicinal properties. Ginger has been shown to reduce the severity of several diseases, especially of the gastrointestinal system, and studies have clearly indicated that the various extracts of ginger and its principal phytochemicals – gingerols, zingerone, shogaols, and paradols – have a protective role in gastric ailments and irritations such ulcers, vomiting, nausea, dyspepsia, stomach ache, spasm, and gastrointestinal cancer. This chapter summarizes the traditional and scientific observations of the gastrointestinal protective effect of ginger. It also addresses the lacunae in these published studies, and emphasizes the need for further investigations so ginger can be used in clinics in the future.