IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway.

Abstract

Mediterranean spotted fever due to infection by Rickettsia conorii, is characterized by a general vasculitis. This vasculitis is thought to be due to a direct injury to endothelial cells induced by R. conoryi However, production and activity of cytokines on endothelial cells is an important pathway in inflammation, and part of the underlying mechanism of vasculitis. In the present studies, human umbilical vein endothelial cells (HUVEC) infected with R. conorii actively secrete high levels of IL-8 and IL-6 (P < 0.002, and P < 0.03, respectively, compared with uninfected cells). IL-la, IL1j3, or TNFa were not detected in the culture supernates.Nevertheless, IL-6 and IL-8 production was due, in a large part, to a cell-associated form of IL-la expressed on R. conorii-infected HUVEC, since production of these cytokines was suppressed by 80% (P = 0.0001) and 85% (P < 0.04) by the addition of IL-1 receptor antagonist, or anti-IL-la antibodies (60% inhibition, P < 0.01 and 65% inhibition, P < 0.05, respectively) and IL-la was measured after lysis of R. conorii-infected HUVEC but not in uninfected cells (P < 0.01). Rickettsial lipopolysaccharide does not seem to be involved, since polymyxin B did not reduce cytokine secretion. On the contrary, infection by intracellular R. conorii appears to be necessary to induce IL-la and subsequently IL-8, since formalin-fixed R. conorii did not induce cytokine production. These observations demonstrate that R. conorii-infected HUVEC secrete IL-6 and IL-8 via the induction of cell-associated IL-la, providing a possible mechanism for the vasculitis observed in Mediterranean spotted fever. (J. Clin. Invest. 1995Invest. . 96:2839Invest. -2844

Secretion of proinflammatory cytokines by epithelial cells in response to Chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis.

“…IL-1␣ released from Chlamydia-infected cells was an important agonist for proinflammatory cytokine secretion by the cervical epithelial cell lines. A similar role for IL-1␣ has been reported in the induction of the proinflammatory cytokine response of cultured epithelial and stromal cells to the cytolytic protozoan parasite Entamoeba histolytica (39), and for the endothelial cell response to Rickettsia conorii (47). Whereas E. histolytica causes cell lysis of infected monolayers and release of preformed cellular IL-1␣ within 2-4 h after infection, that is paralleled by the increased secretion of proinflammatory cytokines (39), cell lysis following chlamydial infection is relatively slow and requires several days to occur.…”

Chlamydia trachomatis Infection of Epithelial Cells Induces the Activation of Caspase-1 and Release of Mature IL-18

“…Several reports have suggested that proinflammatory cytokines can be released from infected epithelial cells following host cell lysis after infection (27)(28)(29). Chlamydiae replicate in a specialized vacuole in the host cell cytoplasm and induce host cell lysis at the end of its developmental cycle (30).…”

“…Little is known of how a microbial pathogen might regulate IL-18 secretion from epithelial cells. IL-1␣ is an upstream cytokine that regulates the de novo production of other proinflammatory cytokines and chemokines, such as IL-8, IL-6, GM-CSF, growth-regulated oncogene-␣, and TNF-␣, from epithelial cells or endothelial cells infected with microbial pathogens such as C. trachomatis (22), Rickettsia conorii (28), Entamoeba histolytica (27), Toxoplasma gondii (29), and respiratory syncytial virus (32). Our observations demonstrate that increased IL-18 secretion in epithelial cells after C. trachomatis infection is not mediated by IL-1␣ or other secreted factor(s), indicating that IL-18 secretion from epithelial cells infected with chlamydia differs from that regulating the secretion of IL-8, IL-6, GM-CSF, TNF-␣, and other proinflammatory cytokines or chemokines.…”

A revised model for the secretion of tPA and cytokines from cultured endothelial cells

“…To address whether the tPA organelle might represent a common compartment for inflammatory molecules in ECs exposed to proinflammatory cytokines, we determined the subcellular localization of IL-6, whose endogenous levels are also up-regulated by IL-1 [27][28][29] (and supplemental Figure 1Aii). After IL-1␤ treatment, a large increase in IL-6-specific immunoreactivity was seen in the Golgi region, small puncta, and numerous WPBs (supplemental Figure 4B-C).…”