The purpose of this study was to evaluate serum leptin levels in systemic lupus erythematosus (SLE). Forty-one women with SLE were compared with 23 healthy women of similar age and body mass index (BMI). Clinical characteristics and Mexican systemic lupus erythematosus disease activity index (Mex-SLEDAI) score were assessed. Serum leptin levels (ng/dl) were measured by enzyme-linked immunosorbent assay (ELISA). Comparisons of leptin levels were made with the Mann-Whitney U-test. In a multiple regression analysis, those factors that could influence the leptin levels were adjusted. Patients with SLE had higher leptin levels than the control group (SLE median 31 vs control median 15, P=0.023). After adjusting by other variables, the serum leptin levels remained higher in SLE than in controls (P=0.02). Patients with SLE had no association between leptin levels and Mex-SLEDAI score, age, duration of disease, or prednisone doses. Those with SLE had higher leptin levels than controls. Further longitudinal studies are required to evaluate the role of this hormone in the exacerbations of SLE.

Inflammatory mediators derived from arachidonic acid (AA) alter the function of dendritic cells (DC), but data regarding their biosynthesis resulting from stimulation of opsonic and nonopsonic receptors are scarce. To address this issue, the production of eicosanoids by human monocyte-derived DC stimulated via receptors involved in Ag recognition was assessed. Activation of FcγR induced AA release, short-term, low-grade PG biosynthesis, and IL-10 production, whereas zymosan, which contains ligands of both the mannose receptor and the human β-glucan receptor dectin-1, induced a wider set of responses including cyclooxygenase 2 induction and biosynthesis of leukotriene C4 and IL-12p70. The cytosolic phospholipase A2 inhibitor pyrrolidine 1 completely inhibited AA release stimulated via all receptors, whereas the spleen tyrosine kinase (Syk) inhibitors piceatannol and R406 fully blocked AA release in response to immune complexes, but only partially blocked the effect of zymosan. Furthermore, anti-dectin-1 mAb partially inhibited the response to zymosan, and this inhibition was enhanced by mAb against DC-specific ICAM-3-grabbing nonintegrin (SIGN). Immunoprecipitation of DC lysates showed coimmunoprecipitation of DC-SIGN and dectin-1, which was confirmed using Myc-dectin-1 and DC-SIGN constructs in HEK293 cells. These data reveal a robust metabolism of AA in human DC stimulated through both opsonic and nonopsonic receptors. The FcγR route depends on the ITAM/Syk/cytosolic phospholipase A2 axis, whereas the response to zymosan involves the interaction with the C-type lectin receptors dectin-1 and DC-SIGN. These findings help explain the distinct functional properties of DC matured by immune complexes vs those matured by β-glucans.

Compared with controls, patients displayed an inflammatory phenomenon before receiving RT. Serum CRP decreased significantly after RT, whereas TNFalpha and IL-6 increased.

Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis. As with animal findings, the frequency of pDCs in the lungs of patients with systemic sclerosis correlated with the severity of lung disease and with the frequency of CD4+ and IL-4+ T cells in the lung. Finally, treatment with imatinib that has been reported to reduce and/or prevent deterioration of skin and lung fibrosis profoundly reduced pDCs in lungs but not in peripheral blood of patients with systemic sclerosis. These observations suggest a role for pDCs in the pathogenesis of systemic fibrosis and identify the increased trafficking of pDCs to the affected organs as a potential therapeutic target in fibrotic diseases.

The induction of cyclooxygenase-2 (COX-2) and the production of PGE2 in response to pathogen-associated molecular patterns decorated with mannose moieties were studied in human monocytes and monocyte-derived macrophages (MDM). Saccharomyces cerevisiae mannan was a robust agonist, suggesting the involvement of the mannose receptor (MR). MR expression increased along the macrophage differentiation route, as judged from both its surface display assessed by flow cytometry and the ability of MDM to ingest mannosylated BSA. Treatment with mannose-BSA, a weak agonist of the MR containing a lower ratio of attached sugar compared with pure polysaccharides, before the addition of mannan inhibited COX-2 expression, whereas this was not observed when agonists other than mannan and zymosan were used. HeLa cells, which were found to express MR mRNA, showed a significant induction of COX-2 expression upon mannan challenge. Conversely, mannan did not induce COX-2 expression in HEK293 cells, which express the mRNA encoding Endo180, a parent receptor pertaining to the MR family, but not the MR itself. These data indicate that mannan is a strong inducer of COX-2 expression in human MDM, most likely by acting through the MR route. Because COX-2 products can be both proinflammatory and immunomodulatory, these results disclose a signaling route triggered by mannose-decorated pathogen-associated molecular patterns, which can be involved in both the response to pathogens and the maintenance of homeostasis.

The release of arachidonic acid (AA) in response to microorganism-derived products acting on pattern recognition receptors (PRR) was assayed in human polymorphonuclear leukocytes (PMN). Peptidoglycan (PGN) and mannan were found to be strong inducers of AA metabolism, as they produced the release of AA at a similar extent to that produced by agonists of pathophysiological relevance such as complement-coated zymosan particles and IgG immune complexes. In sharp contrast, lipoteichoic acid, LPS, muramyldipeptide, and the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4 failed to do so. Leukotriene B4 and PGE2 were synthesized in response to mannan and PGN, thus suggesting that the lipoxygenase and the cyclooxygenase routes are operative in human PMN in response to pathogen-associated molecular patterns (PAMP). Analysis of the lipid extracts of supernatants and cell pellets as well as pharmacological studies with the calpain inhibitor calpeptin and the cytosolic phospholipase A2 (PLA2) inhibitor pyrrolidine-1 showed the dependence of AA release on cytosolic PLA2-catalyzed reactions. The effect of PGN was not inhibited by previous treatment with anti-TLR2 mAb, thus suggesting a nonarchetypal involvement of the TLR2 signaling route and/or participation of other receptors. Because of the abundance of mannose-based and PGN-containing PAMP in fungi and bacteria and the wide array of PRR in human PMN, these finding disclose a role of prime importance for PAMP and PRR in AA metabolism in the inflammatory response mediated by PMN.

The variable array of pattern receptor expression in different cells of the innate immune system explains the induction of distinct patterns of arachidonic acid (AA) metabolism. Peptidoglycan and mannan were strong stimuli in neutrophils, whereas the fungal extract zymosan was the most potent stimulus in monocyte-derived dendritic cells since it induced the production of PGE2, PGD2, and several cytokines including a robust IL-10 response. Zymosan activated κB-binding activity, but inhibition of NF-κB was associated with enhanced IL-10 production. In contrast, treatments acting on CREB (CRE binding protein), including PGE2, showed a direct correlation between CREB activation and IL-10 production. Therefore, in dendritic cells zymosan induces il10 transcription by a CRE-dependent mechanism that involves autocrine secretion of PGE2, thus unraveling a functional cooperation between eicosanoid production and cytokine production.

Background Patients with high peritoneal permeability have the greatest degree of inflammation on continuous ambulatory peritoneal dialysis (CAPD), which may be associated with their higher mortality. Nocturnal intermittent peritoneal dialysis (NIPD; “dry day”) may decrease inflammation by reducing the contact between dialysate and peritoneum and/or providing better fluid overload control. Therefore, the aims of this study were to determine and compare serum and dialysate concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) of patients with high or high-average peritoneal transport on CAPD, changed to NIPD, and ultimately to continuous cyclic peritoneal dialysis (CCPD). Methods Crossover clinical trial in 11 randomly selected patients. All subjects had been on CAPD and were changed to NIPD, and ultimately to CCPD (6.4 ± 3.1 months after initiation of study). All patients used glucose-based dialysate. Evaluations of clinical and biochemical parameters, dialysis adequacy, and serum and dialysis inflammation markers were performed at baseline on CAPD, 7 – 14 days after changing to NIPD, 7 – 14 days after switching to CCPD, and after 1 year of follow-up. All patients used only 1.5% glucose dialysate during evaluation days. CRP was determined by nephelometry, and IL-6 and TNF-α by ELISA. Results Seven patients were high transporters and 4 high average. Ultrafiltration increased ( p < 0.05) when patients changed from CAPD [0.38 L (-0.3 – 1.1 L)] to NIPD [2.64 L (0.7 – 4.7 L)]; it then decreased on CCPD [0.88 L (0.4 – 1.3 L) and at the end of study [0.65 L (0.3 – 1.0 L)]. This better fluid overload control was accompanied by decreased weight and systolic and diastolic blood pressure when patients changed from CAPD (89 ± 13 kg, 160 ± 23 and 97 ± 9 mmHg, respectively) to NIPD (86 ± 17 kg, 145 ± 14 and 86 ± 9 mmHg, respectively), and increased weight and systolic and diastolic blood pressure on CCPD (85 ± 15 kg, 143 ± 23 and 88 ± 14 mmHg, respectively) and at the end of follow-up (87 ± 16 kg, 155 ± 24 and 89 ± 12 mmHg, respectively). Median serum CRP decreased ( p = 0.03), from 3.8 (1.6 – 8.5) mg/L on CAPD to 1.0 (0.4 – 4.4) mg/L on NIPD, but increased on CCPD [1.8 (1.3 – 21) mg/L] and at the end of the study [3.2 (0.3 – 8.2) mg/L]. Dialysate CRP decreased nonsignificantly, from 0.10 (0 – 0.5) mg/L on CAPD to 0 (0 – 0.03) mg/L on NIPD, to 0.01 (0 – 0.08) mg/L on CCPD, and to 0 (0 – 0) mg/L at final evaluation. Serum TNF-α concentration decreased, from 0.14 (0.04 – 0.6) pg/mL on CAPD to 0.01 (0 – 0.08) pg/mL on NIPD, and then increased to 0.06 (0 – 0.4) pg/mL on CCPD and to 0.11 (0 – 0.2) pg/mL at the end of the study; whereas dialysate TNF-α decreased, from 0.08 (0.03 – 0.2) pg/mL on CAPD to 0.04 (0 – 0.2) pg/mL on NIPD, and to 0 (0 – 0) pg/mL and 0 (0 – 0.05) pg/mL on CCPD and final evaluation respectively. Serum IL-6 decreased ( p = 0.07), from 2.5 (2.0 – 4.2) pg/mL on CAPD to 1.0 (0.7 – 2.0) pg/mL on NIPD, and to 1.0 (0.8 – 2.9) pg/mL on CCPD and 1.0 (0.5 – 9.8) pg/mL at the end of the study; whereas dialysate levels remained similar on CAPD [8.0 (3.7 – 13) pg/mL] and NIPD [7.8 (5.1 – 23) pg/mL], and increased on CCPD [11.2 (9.5 – 19) pg/mL] and at final evaluation [11.2 (8.3 – 15) pg/mL]. Conclusions NIPD significantly decreased serum CRP and displayed a trend to decrease TNF-α and IL-6 serum concentrations compared with CAPD; whereas CCPD tended to reverse these effects. These results did not appear to be due to decreased local peritoneal inflammation, but they could be associated with better control of fluid overload on NIPD. Thus, NIPD, as long as the residual renal function allows it, may be useful in reducing the systemic inflammation of patients with high peritoneal membrane permeability.