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B in Leukocyte Recruitment1
*
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
Physiology Program, Harvard School of Public Health, Boston, MA 02115;
Division of Immunology Research, Department of Pathology, Brigham and Women’s Hospital, and Division of Emergency Medicine, Children’s Hospital, Boston, MA 02115;
Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, Boston MA 02111;
¶ Department of Biological Sciences, Columbia University, New York, NY 10027;
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Biogen, Cambridge, MA 02142;
#
California Institute of Technology, Pasadena, CA 91125.
NF-
B binding sites are present in the promoter regions of many
acute phase and inflammatory response genes, suggesting that NF-B
plays an important role in the initiation of innate immune responses.
However, targeted mutations of the various NF-B family members have
yet to identify members responsible for this critical role.
RelA-deficient mice die on embryonic day 15 from TNF-
-induced liver
degeneration. To investigate the importance of RelA in innate immunity,
we genetically suppressed this embryonic lethality by breeding the RelA
deficiency onto a TNFR type 1 (TNFR1)-deficient background.
TNFR1/RelA-deficient mice were born healthy, but were susceptible to
bacterial infections and bacteremia and died within a few weeks after
birth. Hemopoiesis was intact in TNFR1/RelA-deficient newborns, but
neutrophil emigration to alveoli during LPS-induced pneumonia was
severely reduced relative to that in wild-type or TNFR1-deficient mice.
In contrast, radiation chimeras reconstituted with RelA or
TNFR1/RelA-deficient hemopoietic cells were healthy and demonstrated no
defect in neutrophil emigration during LPS-induced pneumonia. Analysis
of RNA harvested from the lungs of mice 4 h after LPS insufflation
revealed that the induction of several genes important for neutrophil
recruitment to the lung was significantly reduced in
TNFR1/RelA-deficient mice relative to that in wild-type or
TNFR1-deficient mice. These results suggest that TNFR1-independent
activation of RelA is essential in cells of nonhemopoietic origin
during the initiation of an innate immune
response.
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