Uropathogenic Escherichia coli -Induced Inflammation Alters Mouse Urinary Bladder Contraction via an Interleukin-6-Activated Inducible Nitric Oxide Synthase-Related Pathway

Abstract

Escherichia coli is the most common cause of urinary tract infection. Elevated blood and urine interleukin-6 (IL-6) levels have been shown in inflammatory urinary tract diseases. The role of IL-6 in mediating the urodynamic dysfunction in response to E. coli-induced urinary tract infection has not yet been fully elucidated. In this study, we investigated the role of IL-6 in the nitric oxide (NO)-triggered alteration of contractile responses in the urinary bladder under an E. coli-induced inflammatory condition. The electrical field stimulation (EFS)-evoked contractions of the isolated detrusor strips, and immunoblotting for detecting protein expression in the bladders was measured short term (1 h) or long term (6 or 24 h) after intraperitoneal injection of E. coli endotoxin (lipopolysaccharide [LPS]) or intravesical instillation of human pyelonephritogenic E. coli-J96 (O4:K6) strain or LPS into mice. IL-6 and NO productions were increased in the urinary bladders of mice 1 to 24 h after LPS or E. coli-J96 treatment. Inducible NO synthase (iNOS) expression and protein kinase C (PKC) activation and EFS-evoked detrusor contractions were increased in the bladders at 6 h after LPS or E. coli-J96 treatment, which could be reversed by anti-IL-6 antibody and iNOS inhibitor aminoguanidine. At 1 h after LPS administration, bladder NO generation, endothelial NOS expression, and EFS-evoked detrusor contractions were effectively increased, whereas anti-IL-6 antibody could not reverse these LPS-induced responses. These results indicate that IL-6 may play an important role in the iNOS/NOtriggered PKC-activated contractile response in urinary bladder during E. coli or LPS-induced inflammation.Urinary tract infections have been estimated that are the common infection acquired in hospitalized adult patients with a prevalence of 1 to 10% representing 30 to 40% of all nosocomial infections (4, 10, 14, 37). The development of urinary tract infections, including cystitis and pyelonephritis, in critically ill adult patients has been associated with considerable morbidity, prolonged hospitalization, and greater healthcare expenditures (4, 10). Urinary tract infections can also be a significant source of morbidity in the pediatric population (32). Escherichia coli is the most common cause of urinary tract infection (35). Increased frequency of micturition is a common symptom of urinary tract infection (20). The exact mechanisms of the symptoms of urinary tract infection are poorly understood.Inflammation plays a role in most bladder pathologies (7,30,38). Infection of the urinary tract results in an inflammatory response characterized by increased levels of urinary cytokines and neutrophil influx (2, 6). In rodent or mouse urinary tract infection models, which involved treatment with E. coli lipopolysaccharide (LPS) by intravesical instillation or intraperitoneal injection, induced interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expressions occurred within 4 to 24 h (9,23,29). It has been found that intravesical NO donors...

A molecular signature of an arrest of descent in human parturition

“…;220 Muscle-derived IL-6 expression within the contracting muscle increases in response to a reduction of intramuscular glycogen content, suggesting that the IL-6 response may be a signal that muscle glycogen stores are being depleted 221222 We report significantly higher myometrial IL-6 mRNA and protein expressions in an arrest of descent compared to spontaneous term labor.…”

Interleukin‐6 levels in female rats with protamine sulfate‐induced chronic cystitis treated with hyaluronic acid

“…22 Furthermore, IL-6 can enhance detrusor smooth muscle contractility, which might result in voiding frequency. 23,24 Lamale et al 13 reported that IL-6 levels increased in patients with IC versus controls, and Erickson et al 12 confirmed this observed correlation between IL-6 and IC, further establishing an association between IL-6 and symptom severity. Peters et al reported that IL-6 levels were elevated in active IC, and patients with IC in remission after receiving BCG had identical IL-6 levels and symptom scores as non-IC control subjects.…”

“…IL‐6 is important to the transition between acute and chronic inflammation, and exhibits a pro‐inflammatory profile in chronic inflammation . Furthermore, IL‐6 can enhance detrusor smooth muscle contractility, which might result in voiding frequency . Lamale et al .…”

Reciprocal Regulation between Proinflammatory Cytokine-induced Inducible NO Synthase (iNOS) and Connexin43 in Bladder Smooth Muscle Cells

“…In a recent report, E. coli-induced bladder inflammation was associated with an increased bladder contractile response, which was mediated by the NO-induced activation of PKC (44). Given that GJs are required for the coordinated contractile response (45), the elevation of Cx43 by NO in BSMCs could exaggerate the abnormal bladder contractile response under inflammatory situations.…”