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Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor.

Höpken UE, Lu B, Gerard NP, Gerard C - J. Exp. Med. (1997)

Bottom Line: We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation.In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model.In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin.

View Article: PubMed Central - PubMed

Affiliation: Ina Sue Perlmutter Cystic Fibrosis Laboratory, Children's Hospital, Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation. In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model. C5aR- deficient mice exhibit decreased migration of neutrophils and decreased levels of TNF-alpha and interleukin 6 in the peritoneal reverse passive Arthus reaction compared to their wild-type littermates. In the reverse passive Arthus reaction in the skin the C5aR was also required for the full expression of neutrophil influx and edema formation; C5aR-deficient mice showed reduced neutrophil migration and microvascular permeability changes. In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin. These data indicate a dominant role for the C5aR and its ligand in the reverse passive Arthus reaction in the lung and a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury.

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C5a-dependent secretion of IL-6. The reverse passive Arthus  reaction (IC) was allowed to proceed for 4 or 8 h in C5aR (−/−) mice  (dotted bars) and their wild-type littermates (black bars). IL-6 content in the  peritoneal fluid was determined by an IL-6–specific ELISA. Ab controls  (Ab control) received Ab to chicken egg albumin i.p. without i.v. injection  of chicken egg albumin. Mice treated with PBS i.p. followed by i.v.  chicken egg albumin served as Ag controls (Ag control). Data are represented as mean ± SEM, n = 14–17 mice (4 h) and n = 7–9 mice (8 h).  *P <0.004.
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Figure 3: C5a-dependent secretion of IL-6. The reverse passive Arthus reaction (IC) was allowed to proceed for 4 or 8 h in C5aR (−/−) mice (dotted bars) and their wild-type littermates (black bars). IL-6 content in the peritoneal fluid was determined by an IL-6–specific ELISA. Ab controls (Ab control) received Ab to chicken egg albumin i.p. without i.v. injection of chicken egg albumin. Mice treated with PBS i.p. followed by i.v. chicken egg albumin served as Ag controls (Ag control). Data are represented as mean ± SEM, n = 14–17 mice (4 h) and n = 7–9 mice (8 h). *P <0.004.

Mentions: It has been shown that immune complexes also induce the secretion of IL-6 and IL-10 from human monocytes (24). To test the role of the C5aR and its ligand in regulating IL-6 synthesis in immune complex peritonitis we measured IL-6 levels in the peritoneal lavage samples of C5aR (−/−) and wild-type animals 4 and 8 h after challenge. As demonstrated in Fig. 3, remarkable IL-6 levels were measurable at 4 h (wild type: 16.43 ± 3.62 ng/ml IL-6 [mean ± SEM]; C5aR [−/−]: 5.72 ± 2.42 ng/ml IL-6 [mean ± SEM]) and to a lesser extent at 8 h (wild type: 1.88 ± 0.74 IL-6 [mean ± SEM]; C5aR [−/−]: 0.97 ± 0.18 ng/ml IL-6 [mean ± SEM]). No detectable levels of IL-6 were found in Ag controls. In the exudate from C5aR (−/−) mice the IL-6 levels were significantly reduced compared to their wild-type controls at 4 h (65.2%), whereas the decrease in IL-6 levels in the C5aR (−/−) mice at 8 h (34.8%) did not reach statistical significance. These results suggest that C5a enhances IL-6 secretion mainly in the earlier phase of immune complex–induced inflammation in the peritoneum.


Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor.

Höpken UE, Lu B, Gerard NP, Gerard C - J. Exp. Med. (1997)

C5a-dependent secretion of IL-6. The reverse passive Arthus  reaction (IC) was allowed to proceed for 4 or 8 h in C5aR (−/−) mice  (dotted bars) and their wild-type littermates (black bars). IL-6 content in the  peritoneal fluid was determined by an IL-6–specific ELISA. Ab controls  (Ab control) received Ab to chicken egg albumin i.p. without i.v. injection  of chicken egg albumin. Mice treated with PBS i.p. followed by i.v.  chicken egg albumin served as Ag controls (Ag control). Data are represented as mean ± SEM, n = 14–17 mice (4 h) and n = 7–9 mice (8 h).  *P <0.004.
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Related In: Results  -  Collection

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Figure 3: C5a-dependent secretion of IL-6. The reverse passive Arthus reaction (IC) was allowed to proceed for 4 or 8 h in C5aR (−/−) mice (dotted bars) and their wild-type littermates (black bars). IL-6 content in the peritoneal fluid was determined by an IL-6–specific ELISA. Ab controls (Ab control) received Ab to chicken egg albumin i.p. without i.v. injection of chicken egg albumin. Mice treated with PBS i.p. followed by i.v. chicken egg albumin served as Ag controls (Ag control). Data are represented as mean ± SEM, n = 14–17 mice (4 h) and n = 7–9 mice (8 h). *P <0.004.
Mentions: It has been shown that immune complexes also induce the secretion of IL-6 and IL-10 from human monocytes (24). To test the role of the C5aR and its ligand in regulating IL-6 synthesis in immune complex peritonitis we measured IL-6 levels in the peritoneal lavage samples of C5aR (−/−) and wild-type animals 4 and 8 h after challenge. As demonstrated in Fig. 3, remarkable IL-6 levels were measurable at 4 h (wild type: 16.43 ± 3.62 ng/ml IL-6 [mean ± SEM]; C5aR [−/−]: 5.72 ± 2.42 ng/ml IL-6 [mean ± SEM]) and to a lesser extent at 8 h (wild type: 1.88 ± 0.74 IL-6 [mean ± SEM]; C5aR [−/−]: 0.97 ± 0.18 ng/ml IL-6 [mean ± SEM]). No detectable levels of IL-6 were found in Ag controls. In the exudate from C5aR (−/−) mice the IL-6 levels were significantly reduced compared to their wild-type controls at 4 h (65.2%), whereas the decrease in IL-6 levels in the C5aR (−/−) mice at 8 h (34.8%) did not reach statistical significance. These results suggest that C5a enhances IL-6 secretion mainly in the earlier phase of immune complex–induced inflammation in the peritoneum.

Bottom Line: We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation.In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model.In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin.

View Article: PubMed Central - PubMed

Affiliation: Ina Sue Perlmutter Cystic Fibrosis Laboratory, Children's Hospital, Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation. In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model. C5aR- deficient mice exhibit decreased migration of neutrophils and decreased levels of TNF-alpha and interleukin 6 in the peritoneal reverse passive Arthus reaction compared to their wild-type littermates. In the reverse passive Arthus reaction in the skin the C5aR was also required for the full expression of neutrophil influx and edema formation; C5aR-deficient mice showed reduced neutrophil migration and microvascular permeability changes. In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin. These data indicate a dominant role for the C5aR and its ligand in the reverse passive Arthus reaction in the lung and a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury.

Show MeSH
Related in: MedlinePlus