Elevated formation of bradykinin (BK) and Lys-BK or kallidin (KD) and their carboxypeptidase metabolites desArg(9)BK and desArg(10)KD is evident at sites of inflammation. Moreover, B2 receptors (B2R), which mediate the action of BK and KD, participates in the acute stage of the inflammatory and pain response, whereas B1 receptors (B1R), through which desArg(9)BK and desArg(10)KD act, partake in the chronic stage. We hypothesized that kinins autoregulate B2R and B1R expression in favor of B1R. Incubation of IMR-90 cells with BK (100 nM) led to a loss (89%) of B2R with a half-life (T(1/2)) of 7.0 min. Concomitantly, BK increased B1R (2- to 3-fold) with a T(1/2) of 120 min. DesArg(10)KD (100 nM) had no effect on B2R but increased B1R (3- to 4-fold) with the same rate as BK. Interleukin-1beta (IL-1beta; 500 pg/ml) also increased B1R (4- to 6-fold). Although both desArg(10)KD and BK increased the level of IL-1beta mRNA, IL-1beta receptor antagonist inhibited the increase in B1R only in response to BK. DesArg(10)KD and BK synergistically increased B1R (9-fold), which was further increased by inclusion of IL-1beta (36-fold). Therefore, kinin metabolism and kinin-stimulated production of cytokines may play a pivotal role in shifting the repertoire of kinin receptor subtypes in favor of B1R during inflammation.

Burkholderia cepacia is a prevalent pulmonary pathogen in patients with cystic fibrosis (CF). The lung pathology observed in patients with CF is postulated to be due to an overexpression of chemokines. This study investigated the induction of the neutrophil chemoattractant chemokine IL-8 and the signaling pathways activated by B. cepacia-infected human lung epithelial A549 (HLE) cells. Cells were infected with B. cepacia (genomovar III of the B. cepacia complex), and reverse transcriptase-PCR and ELISA for the cytokines were performed. B. cepacia (multiplicity of infection Ն4:1) induced HLE cells to significantly secrete IL-8 in a more potent manner than the predominant CF pathogen Pseudomonas aeruginosa (multiplicity of infection Ն64:1 Cystic fibrosis (CF) is the most common lethal genetic disease of white individuals (1). Exaggerated and persistent chronic inflammation caused by microbial colonization of the major airways is thought to be one of the major causes of morbidity and mortality in patients with CF (2). One of the major organisms to infect patients with CF is Pseudomonas aeruginosa. However, in recent years, the multidrug-resistant pulmonary pathogen Burkholderia cepacia has become increasingly prevalent in these patients (3

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An inappropriate host response to invading bacteria is a critical parameter that often aggravates the outcome of an infection. Staphylococcus aureus is a major human Gram-positive pathogen that causes a wide array of community-and hospital-acquired diseases ranging from superficial skin infections to severe conditions such as staphylococcal toxic shock. Here we find that S aureus induces inflammatory reactions by modulating the expression and response of the B1 and B2 receptors, respectively. This process is initiated by a chain of events, involving staphylococcal-induced cytokine release from monocytes, bacteriatriggered contact activation, and conversion of bradykinin to its metabolite IntroductionStaphylococcus aureus, an important opportunistic Gram-positive human pathogen, is the most common organism isolated from soft-tissue and wound infections. The bacterium can cause a variety of community-and hospital-acquired diseases ranging from relatively benign skin infections, such as furuncles and subcutaneous abscesses, to more severe conditions, including scaled skin syndrome, necrotizing pneumonia, endocarditis, sepsis, and staphylococcal toxic shock syndrome (for reviews, see Lowy 1 and Yarwood and Schlievert 2 ). In severe conditions, staphylococci may evoke an inappropriate inflammatory host response by modulating so-called host effector systems. For instance, S aureus produces a diverse range of virulence factors contributing to the inflammatory response, among others the enterotoxins and toxic shock syndrome toxin-1 (TSST-1) that form a class of substances also known as pyrogenic toxin superantigens or PTSAgs (for a review, see Balaban and Rasooly 3 ). PTSAgs can induce a profound inflammatory reaction by interacting with MHC class II molecules and T-cell antigen receptors disengaged from the normal antigen-specific signal transduction of T cells. 4,5 The resulting inflammatory response is by far greater than antigen-specific activation and leads to pathologic levels of proinflammatory cytokines. 6 The human contact system, also known as the kallikrein-kinin cascade or intrinsic pathway of coagulation, is another example of a system that can be targeted and affected during infection. 7 The contact system consists of 4 factors, 3 serine proteinases (coagulation factors XI and XII, and plasma kallikrein), and 1 nonenzymatic cofactor (high-molecular-weight kininogen). Normally, these factors circulate as zymogens in the bloodstream. Contact activation can occur for instance on newly exposed cellular surfaces and is regulated by limited proteolysis. The initial step is activation of coagulation factor XII, which converts plasma kallikrein into the active form. Active kallikrein in turn amplifies the activation of factor XII, eventually resulting in clot formation, and the release of bradykinin (BK) from the precursor molecule, high-molecularweight kininogen. Previous studies have shown an interaction between S aureus and the contact system leading to its activation at the bacterial surface. 8 As a result, B...