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. 1998 Apr 28;95(9):5257-62.
doi: 10.1073/pnas.95.9.5257.

Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state

H Hakonarson  1 , M M Grunstein
Affiliations

Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state

H Hakonarson et al. Proc Natl Acad Sci U S A. .

Abstract

To elucidate the role of IgE-dependent mechanisms in inducing altered airway responsiveness in the atopic asthmatic state, the expression and actions of Fc receptor activation were examined in isolated rabbit tracheal smooth muscle (TSM) tissue and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic-sensitized TSM exhibited significantly increased maximal isometric contractility to acetylcholine (P < 0. 01) and attenuated maximal relaxation responses and sensitivity (i.e.,-log ED50) to isoproterenol (P < 0.005). These changes in agonist responsiveness in atopic sensitized TSM were ablated by pretreating the tissues with a blocking mAb to the low affinity receptor for IgE, FcepsilonRII (i.e., CD23) or by depleting the sensitizing serum of its immune complexes. Moreover, in complimentary experiments, exogenous administration of IgE immune complexes to naive TSM produced changes in agonist responsiveness that were qualitatively similar to those obtained in the atopic asthmatic-sensitized state. Extended studies further demonstrated that, in contrast to their respective controls, atopic asthmatic serum-sensitized human and rabbit TSM tissue and cultured cells exhibited markedly induced mRNA and cell surface expression of FcepsilonRII, whereas constitutive expression of the IgG receptor subtype, FcgammaRIII, was unaltered. Finally, the up-regulated mRNA expression of FcepsilonRII observed following exposure of TSM to atopic asthmatic serum or to exogenously administered IgE immune complexes was significantly inhibited by pretreating the tissues or cells with anti-CD23 mAb. Collectively, these observations provide evidence demonstrating that the altered agonist responsiveness in atopic asthmatic sensitized airway smooth muscle is largely attributed to IgE-mediated induction of the autologous expression and activation of FcepsilonRII receptors in the airway smooth muscle itself.

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Figures

Figure 1
Figure 1
(A) Comparison of contractile dose–response relationships to ACh in paired control serum-treated (○) and atopic asthmatic serum-treated TSM segments in the absence (•) and presence (□) of anti-CD23 mAb. (B) Comparison of contractile dose-response relationships to ACR in control serum-treated (○) and atopic asthmatic serum-treated TSM in the absence (•) and presence (□) of SpA. Data represent mean ± SE values from six paired tissue samples.
Figure 2
Figure 2
(A) Comparison of relaxation dose-relationships to isoproterenol in paired control serum-treated (○) and atopic asthmatic serum-treated TSM segments in the absence (•) and presence (□) of anti-CD23 mAb. (B) Comparison of relaxation responses to isoproterenol in control (○) and atopic asthmatic serum-treated TSM in the absence (•) and presence (□) of SpA. Data are mean ± SE values from eight paired tissue samples.
Figure 3
Figure 3
Comparison of airway constrictor responses to ACh in isolated paired TSM segments in the absence (○) and presence (•) of IgE immune complexes (see Materials and Methods).
Figure 4
Figure 4
Comparison of airway relaxation responses to isoproterenol in paired TSM segments in the absence (○) and presence (•) of human IgE immune complexes (see Materials and Methods).
Figure 5
Figure 5
Comparison of expression of FcγRIII (A) and FcɛRII (CD23) (B) receptor mRNAs by using RT-PCR in rabbit ASM cells after 0, 6-, and 24-hr treatment with 10% control serum and 10% atopic asthmatic sensitizing serum. Expression of α-actin was used to control for loading. cDNA from activated U937 cells (i.e., for FcγRIII) and the immortalized human B-cell line 8.1.6 (i.e., for FcɛRII) were used as positive controls. Note in contrast to FcγRIII, expression of FcɛRII is significantly up-regulated at 24 hr (i.e., >2-fold) after treatment with atopic asthmatic serum.
Figure 6
Figure 6
Representative Southern blots probed with full-length FcγRIII (A), FcɛRII (B), and 157-bp RPL7 human cDNA probes. Paired human ASM samples were incubated with control (CO) or atopic asthmatic (SE) serum for 24 hr. cDNA was transcribed from total RNA primed with oligo(dT). PCR products were amplified by using human-specific FcγRIII, FcɛRII, and RPL7 primers, and then probed. Note the marked induction of FcɛRII expression in the atopic asthmatic serum-sensitized sample (i.e., >7.5-fold), whereas expression of FcγRIII or RPL7 was similar in both samples.
Figure 7
Figure 7
Comparison of expression of FcɛRII mRNA in human bronchial smooth muscle tissue after 24-hr treatment with control (CO) or atopic asthmatic serum in the absence (SE) and presence (SE+) of anti-CD23 mAb. The products of the RT-PCRs with 2.5 μg of total RNA and human-specific primers for the FcɛRII receptor mRNA are shown. Expression of RPL7 was used to control for gel loading. Note that the anti-CD23 mAb significantly attenuated the induction of FcɛRII mRNA expression at 24 hr in atopic asthmatic-serum sensitized ASM.
Figure 8
Figure 8
(A) Comparison of expression of FcɛRII in rabbit ASM cells after 0 and 24-hr treatment with media alone (control) or with IgE immune complexes for 0, 6, 12, and 24 hr. The products of RT-PCRs with 2.5 μg of total RNA and human-specific primers for the FcɛRII receptor mRNA are shown. mRNA expression of α-actin is also shown for comparison. (B) Corresponding time-dependent changes in FcɛRII/α-actin ratio, expressed as fold increase above baseline (i.e., time 0) in control (open bars) and IgE immune complex-treated cells (filled bars). Note the progressive induction of FcɛRII mRNA expression up to 24 hr after treatment with IgE immune complexes, and inhibition of FcɛRII expression at 24 hr in the presence of anti-CD23 mAb (hatched bar).
Figure 9
Figure 9
Flow cytometric analysis of FcγRIII and FcɛRII surface expression in rabbit ASM cells. Cells treated for 24 hr with either 10% control serum or 10% atopic asthmatic serum were stained with FITC-conjugated human mAbs specific for the low-affinity FcγRIII (A) and FcɛRII (CD23) (B) receptors. Activated B-cells (8.1.6) were used as a positive control for the CD23 receptor. The level of nonspecific background staining was measured in both the control- and atopic asthmatic- serum-treated cells by staining with FITC-conjugated isotype control antibodies. Note that the rabbit ASM cells express surface protein for both FcγRIII and FcɛRII receptors. In contrast to FcγRIII receptor expression, which is unaltered in the presence of atopic asthmatic serum, expression of the FcɛRII receptor is increased by >2-fold (i.e., from 17 to 36% in the presence of atopic asthmatic serum.
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