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Autocrine induction of macrophage synthesis of complement subcomponent C1q by endogenous interferon-alpha/beta
M Kolosov1, I Kolosova, A Zhou
1Oklahoma Medical Research Foundation, Noble Center for Biomedical Research, Oklahoma City 73104-5046, USA.
Abstract:
Peritoneal macrophages (M phi) constitutively synthesize and secrete interferon-alpha (IFN-alpha) and IFN-beta, as well as complement subcomponent C1q. Because exogenous interferon-gamma (IFN-gamma) stimulates Mø synthesis of C1q, our purpose was to determine if endogenous secretion of IFN-alpha/beta regulated the constitutive level of endogenous C1q mRNA synthesis in an autocrine fashion. Both exogenous IFN-alpha and IFN-beta effectively substituted for IFN-gamma in stimulating M phi C1q mRNA expression in a dose-dependent fashion by northern blot analysis. Neutralizing anti-INF-alpha/beta antibodies inhibited M phi constitutive C1q mRNA synthesis by approximately twofold and abrogated the feedback stimulatory effects of exogenous C1q on C1q mRNA expression. Paraffin oil-elicited inflammatory M phi displayed distinctively different constitutive levels of C1q mRNA expression from thioglycollate brothelicited M phi, which was correlated with their relative levels of secretory IFN-alpha/beta by ELISA. Exogenous IFN-alpha/beta also restored C1q mRNA synthesis of AKR mouse M phi with low constitutive C1q mRNA expression. The cumulative results support the concept that constitutive synthesis of C1q by M phi is regulated by the endogenous synthesis and secretion of IFN-alpha/beta, which appears to act in an autocrine fashion.
Insights
Macrophages synthesize complement C1q, regulated by their own interferon-alpha/beta (IFN-α/β) in an autocrine manner. This finding reveals a novel regulatory loop for C1q production in macrophages.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Peritoneal macrophages (M phi) constitutively produce interferon-alpha (IFN-α) and interferon-beta (IFN-β).
- These macrophages also synthesize and secrete complement subcomponent C1q.
- Interferon-gamma (IFN-γ) is known to stimulate M phi synthesis of C1q.
Purpose of the Study:
- To investigate if endogenous IFN-α/β regulates constitutive C1q mRNA synthesis in M phi via autocrine signaling.
- To determine the role of endogenous type I interferons in controlling C1q production.
Main Methods:
- Northern blot analysis to assess C1q mRNA expression.
- ELISA to measure secretory IFN-α/β levels.
- Treatment with exogenous IFN-α, IFN-β, and neutralizing anti-IFN-α/β antibodies.
Main Results:
- Exogenous IFN-α and IFN-β stimulated M phi C1q mRNA expression in a dose-dependent manner.
- Neutralizing anti-IFN-α/β antibodies reduced constitutive M phi C1q mRNA synthesis by twofold.
- Different M phi populations (paraffin oil-elicited vs. thioglycollate-elicited) showed varied C1q mRNA levels correlated with IFN-α/β secretion.
- Exogenous IFN-α/β restored C1q mRNA synthesis in M phi with low constitutive levels.
Conclusions:
- Constitutive C1q synthesis by macrophages is regulated by endogenous IFN-α/β.
- This regulation appears to occur through an autocrine mechanism, where secreted IFN-α/β acts on the same macrophage.
- The findings elucidate a novel autocrine pathway controlling C1q production in macrophages.