The functional significance behind expressing two IL-8 receptor types on PMN.

PMN are critical to innate immunity and are fundamental to antibacterial defense. To localize to sites of infection, PMN possess receptors that detect chemoattractant stimuli elicited at the site, such as chemokines, complement split products, or bioactive lipids. Signaling through these receptors stimulates chemotaxis toward the site of infection but also activates a number of biochemical processes, with the result that PMN kill invading bacteria. PMN possess two receptors, CXCR1 and CXCR2, for the N-terminal ELR motif-containing CXC chemokines, although only two chemokine members bind both receptors and the remainder binding only CXCR2. This peculiar pattern in receptor specificity has drawn considerable interest and investigation into whether signaling through each receptor might impart unique properties on the PMN. Indeed, at first glance, CXCR1 and CXCR2 appear to be functionally redundant; however, there are differences. Considering these proinflammatory activities of activating PMN through chemokine receptors, there has been great interest in the possibility that blocking CXCR1 and CXCR2 on PMN will provide a therapeutic benefit. The literature examining CXCR1 and CXCR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.

Role of TNF receptors, TNFR1 and TNFR2, in dextran sodium sulfate-induced colitis.

BACKGROUND: In this study we determined the consequence of the absence of each TNF receptor, TNFR1 or TNFR2, in the dextran sulfate sodium (DSS) model of colitis. METHODS: Wildtype (WT), TNFR1(-/-) and TNFR2(-/-) mice were fed 3% w/v DSS in drinking water for 5 days followed by 2 (day 7) or 7 (day 12) days of tap water. RESULTS: The colons from untreated TNFR1(-/-) and TNFR2(-/-) mice were histologically normal. Following DSS, all strains became inflamed. TNFR1(-/-) mice had a more severe clinical score at days 8 and 9 compared to WT and TNFR2(-/-) mice despite similar histopathological damage in their colons. The more severe clinical score was associated with a reduced macrophage infiltration into the colonic mucosa. TNFR2(-/-) mice showed increased indicators of disease including increased colon weight, a shrunken cecum, and an increased number of ulcers compared to TNFR1(-/-) and WT strains at day 7. Mucosal levels of TNFR2 were elevated in colitic mice compared to uninflamed controls, with no difference between strains on day 7 but on day 12, unlike WT mice, levels were reduced in TNFR1(-/-) mice. There was no difference in the number of TUNEL-positive apoptotic colonic epithelial cells between strains, nor in total cleaved caspase 3 levels between strains, measured by Western blot of colon homogenates. CONCLUSIONS: While deficiency of either receptor contributes to some measures of DSS colitis, the histopathological scores are similar, indicating that TNF receptors either do not play a major role or are redundant in the pathology associated with DSS colitis.

Therapeutic effect of blocking CXCR2 on neutrophil recruitment and dextran sodium sulfate-induced colitis.

Dextran sodium sulfate (DSS)-induced colitis in mice is characterized by polymorphonuclear neutrophil (PMN) infiltration into the colonic mucosa and lumen. The mechanism by which this occurs is unclear. To begin to understand the mechanism, we determined the role of the PMN chemokine receptor, CXCR2, in DSS-induced colitis by using CXCR2(-/-) mice or by neutralizing CXCR2. DSS was administered through drinking water to CXCR2(-/-) and BALB/c mice for 5 days followed by regular water for 1 day. In the neutralization study, mice were injected with control serum or goat anti-CXCR2 antiserum. BALB/c mice receiving DSS and control serum-injected mice receiving DSS lost weight and showed considerable clinical illness. Histological observation revealed submucosal edema, PMN infiltration into the submucosa and mucosa, extensive crypt damage with abscesses, and ulceration. In contrast, both the CXCR2(-/-) and anti-CXCR2 antiserum-treated mice gained weight and had significantly lower symptom scores. Histology of these mice showed submucosal edema but relatively intact crypt architecture and very few ulcers. Significantly fewer PMNs were found in the mucosa in anti-CXCR2 anti-serum compared with control serum-injected inflamed mice, but no significant difference in eosinophil infiltration was observed between the groups. Our experiments identify a role for CXCR2 in DSS-induced colitis and suggest that antagonizing CXCR2 provides some therapeutic efficacy, possibly by impeding PMN recruitment into the mucosa. Antagonizing CXCR2 may form the basis for therapeutic drugs directed at controlling colitis.

Diabetes-prone BioBreeding rats do not have a normal immune response when weaned to a diet containing fermentable fibre.

Diet is known to modulate the development of diabetes in diabetes-prone BioBreeding (BBdp) rats. The objective of the present study was to determine the effect of fermentable fibre (FF) on immune function in BBdp and diabetes-resistant BioBreeding (BBdr) rats after weaning. Weanling BBdp (thirty-six to thirty-eight per diet) and BBdr rats (thirty to thirty-two per diet) were fed a nutritionally complete, semi-purified, casein-based diet containing either cellulose (control diet, 8 % w/w) or FF (3.2 % cellulose+4.8 % w/w inulin). At 35 d, the small intestine was excised and lymphocytes isolated from spleen, mesenteric lymph nodes and Peyer's patches. Feeding FF to both BBdr and BBdp rats affected the production of anti-inflammatory cytokines (P=0.02). In BBdr rats, feeding FF compared with cellulose resulted in an increased small intestinal length (P=0.0031), higher proliferative (stimulation) index from both splenocytes (P=0.001) and mesenteric lymph nodes (P=0.04), and an increased proportion of CD8+ T-cells in the Peyer's patches (P=0.003). We did not observe an effect of diet on the number of IgA-bearing cells in the jejunum from BBdr rats. Feeding FF to BBdp rats did not affect the same parameters. BBdp rats had both a higher proportion of B-cells in the Peyer's patches (P=0.01) and a higher number of IgA+ cells in the jejunum (P=0.0036) when fed a diet containing FF, a response not observed in BBdr rats. We demonstrate that several aspects of the BBdp immune system respond differently than that of BBdr rats when challenged at weaning with FF.