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on Human Eosinophils: II. IL-5 Down-Modulates Its Receptor Via a Proteinase-Mediated Process1
* Allergy and Immunology and
Pulmonary and Critical Care Sections of Department of Medicine, and Departments of
Biomolecular Chemistry and
Pediatrics, University of Wisconsin, Madison, WI 53792; and
¶ Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905
In the accompanying study, we demonstrated that following Ag
challenge, membrane (m)IL-5R
expression is attenuated on
bronchoalveolar lavage eosinophils, soluble (s)IL-5R is detectable
in BAL fluid in the absence of increased steady state levels of
sIL-5R mRNA, and BAL eosinophils become refractory to IL-5 for ex
vivo degranulation. We hypothesized that IL-5 regulates its receptor
through proteolytic release of mIL-5R, which in turn contributes to
the presence of sIL-5R. Purified human peripheral blood eosinophils
were incubated with IL-5 under various conditions and in the presence
of different pharmacological agents. A dose-dependent decrease in
mIL-5R was accompanied by an increase in sIL-5R in the
supernatant. IL-5 had no ligand-specific effect on mIL-5R or
sIL-5R mRNA levels. The matrix metalloproteinase-specific inhibitors
BB-94 and GM6001 and tissue inhibitor of metalloproteinase-3 partially
inhibited IL-5-mediated loss of mIL-5R, suggesting that sIL-5R
may be produced by proteolytic cleavage of mIL-5R. IL-5 transiently
reduced surface expression of 
-chain, but had no effect on the
expression of GM-CSFR. Pretreatment of eosinophils with a dose of
IL-5 that down-modulated mIL-5R rendered these cells unable to
degranulate in response to further IL-5 stimulation, but they were
fully responsive to GM-CSF. These findings suggest that
IL-5-activated eosinophils may lose mIL-5R and release sIL-5R in
vivo, which may limit IL-5-dependent inflammatory events in diseases
such as asthma.
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