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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Investig Med. Author manuscript; available in PMC 2013 January 1.
Published in final edited form as:
PMCID: PMC3335887

Conserved steroid hormone homology converges on NFκB to modulate inflammation in asthma

Asha S. Payne, MD, MPH1,2,3 and Robert J. Freishtat, MD, MPH1,2,3,4


Asthma is a complex, multifactorial disease comprising multiple different subtypes, rather than a single disease entity [1], yet has a consistent clinical phenotype: recurring episodes of chest tightness, wheezing, and difficulty breathing. Despite the complex pathogenesis of asthma, steroid hormones (e.g. glucocorticoids) are ubiquitous in the acute and chronic management of all types of asthma. Overall, steroid hormones are a class of widely-relevant, biologically-active compounds originating from cholesterol and altered in a stepwise fashion, but maintain a basic 17-carbon, 4-ring structure. Steroids are lipophilic molecules that diffuse readily through cell membranes to directly and/or indirectly affect gene transcription. In addition, they employ rapid, non-genomic actions to affect cellular products. Steroid hormones are comprised of several groups (including glucocorticoids, sex steroid hormones, and secosteroids) with critical divergent biological and physiological functions relevant to health and disease. However, the conserved homology of steroid hormone molecules, receptors, and signaling pathways suggest that each of these is part of dynamic system of hormone interaction, likely involving overlap of downstream signaling mechanisms. Therefore, we will review the similarities and differences of these three groups of steroid hormones (i.e. glucocorticoids, sex steroid hormones, and secosteroids), identifying NFκB as a common inflammatory mediator. Despite our understanding of the impact of individual steroids (e.g. glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be better understanding of the interplay of classical, non-classical, and non-genomic steroid hormone function. However, clues from the conserved homology steroid hormone structure and function and signaling pathways, offer insight into a possible model of steroid hormone regulation of inflammation in asthma through common NFκB-mediated downstream events.

Steroid Hormone Receptors

Most steroid hormone effects begin with binding of the hormone to steroid receptors. Each receptor can have multiple isoforms, either encoded by different genes or created via alternative splicing of the same gene. For example, the glucocorticoid receptor (GR)α is more widely expressed in tissues and functions as the “classic” steroid hormone receptor in which binding of the ligand induces expression of glucocorticoid-responsive genes [2]. Meanwhile, GRβ does not bind glucocorticoids but represses the GRα receptor by specifically inhibiting its activation of gene transcription through glucocorticoid response elements (GRE) [3]. It is suspected that increased expression of the GRβ may contribute to steroid-resistant asthma in this manner [4].

Similar to glucocorticoid receptors, estrogen receptors (ER) have two isoforms. Each subtype is differentially expressed, but in tissues co-expressing both receptors, ERβ can inhibit ERα [5] while regulating different genes [6]. In contrast, progesterone receptor B is the more active isoform but can be repressed by progesterone receptor A [7, 8]. The vitamin D (1,25-dihydroxycholecalciferol) receptors also have 2 isoforms [9], but their respective functions are not clear.

Regardless of isoform, all steroid hormone receptors consist of an N-terminal domain, a DNA binding domain, and a variable length hinge region connected to the C-terminal, ligand-binding domain. The glucocorticoid, estrogen, progesterone, and vitamin D receptors all maintain this basic structure [2, 1012]. The N-terminal domain has a variable length and homology, even among the same receptor types [12]. It contains the ligand-independent transcriptional activation function 1 (AF-1), which interacts with molecules important for transcription. Glucocorticoid, estrogen, progesterone, and vitamin D receptors all have AF-1in the N-terminal domain [1214].

The DNA binding domain is the site of genomic interaction and signaling, but also contains components important for receptor homodimerization and nuclear translocation [14, 15]. Though estrogen receptor isoforms have significant structural divergence in the N-terminal domain, they conserve homology between themselves and other steroid hormone receptors in the DNA binding domain [12, 14]. The C-terminal end contains the ligand binding domain, the site for steroid hormone binding. It also contains another transactivation domain, AF-2, which is ligand dependent. The ligand binding domain is important for interaction with transcription factors, but also maintains a role in nuclear localization and dimerization [1521]. Overall, the conserved hormone receptor homology lays the framework of conserved steroid hormone function, including that of downstream signaling.

Classical genomic signaling of steroid hormone receptors

All steroid hormone receptors conserve basic functions: binding of steroid hormones to receptors causes hormone-receptor complexes to translocate to the nucleus, attach to DNA at hormone-specific response elements and, alter gene transcription. This process is often referred to as “classical” steroid hormone genomic signaling (see figure). For example, the GRα exists in the cytosol bound to several associated proteins, including heat-shock proteins and kinases of the mitogen activated protein kinases (MAPK) signaling cascade [22]. When glucocorticoids diffuse into the cell, they bind with high affinity to this receptor, leading to conformational changes and dissociation of the associated proteins. The glucocorticoid-GR complex then translocates to the nucleus and binds as a homodimer to GREs inducing changes in transcription of the corresponding genes. The process is similar for estrogen and progesterone, with estrogen or progesterone-bound receptor homodimers binding to their respective gene response elements. Similarly, 1,25-dihydroxycholecalciferol binds to the vitamin D receptor (VDR) to alter transcription of genes with vitamin D response elements (VDRE) however, it does so not as a homodimer but as a heterodimer with the retinoid X receptor (RXR).

Steroid hormones decrease inflammation by inhibiting NFκB

Binding of steroid-receptor complexes to steroid specific response elements may induce gene transcription or gene repression altering the manifestations and pathogenesis of asthma. For example, glucocorticoid-GR complexes upregulate the transcription of anti-inflammatory genes such IκB, which inhibits NFκB [23]. Similarly, 1,25-dihydroxycholecalciferol also upregulates IκB in airway epithelial cells.[24] The glucocorticoid-GR complexes also suppress transcription of key inflammatory genes, such as IL-1β [25]. Through these anti-inflammatory mechanisms, glucocorticoids decrease pro-inflammatory cytokine release and airway recruitment of inflammatory cells (eosinophils, T lymphocytes, and mast cells) [26, 27].

Non-classical genomic signaling of steroid hormone receptors

In non-classical genomic signaling, steroid hormone-receptor complexes influence transcription without direct binding to their steroid specific DNA response element. Instead, steroid hormone-receptor complexes interact with transcription factors such as NFκB or activator protein (AP)-1 to effect transcription. The glucocorticoid-GR complex can physically bind to AP-1, a pro-inflammatory transcription factor important in asthma [28], leading to transrepression of AP-1 induced genes [29]. Similarly, transrepression occurs when the glucocorticoid-GR complex interacts with the p65 subunit of NFκB [30]. Further, estrogen and progesterone-receptor complexes transrepress through AP-1 and NFκB binding [5, 3135]. VDRs also inhibit NFκB though direct interaction, preventing NFκB translocation to the nucleus[36]. Additional evidence exists for the transrepression of AP-1by the VDR[37]. Cumulatively, glucocorticoids, estrogen, progesterone, and 1,25 dihydroxyvitamin D all mediate transrepression of inflammation via NFκB and AP-1.

Rapid non-genomic effects of steroid hormones

Current literature indicates that steroid hormones also have non-genomic effects. Glucocorticoids, sex steroids, and secosteroids all produce cellular changes too rapidly to be explained by de novo transcription and translation. Within minutes, glucocorticoids inhibit Mek1 and Erk1, members of MAPK pathways[38]. Similarly, the rapid effects of estrogen include activation of signaling cascades leading to ion fluxes, activation of kinases and phosphatases, or other second messengers via a G-protein coupled receptors[39, 40]. The rapid effects seen with progesterone signaling also occur with activation of the MAPK or other kinase families [41]. 1,25 dihydroxyvitamin D also induces rapid, non-genomic responses similar to that of glucocorticoids [42] by mobilizing intracellular calcium [43] and increasing cyclic GMP[44]. Several mechanisms have been proposed to explain the non-genomic actions of all the steroid hormones: 1) physiochemical interactions of hormones with cellular membranes leading to altered changes in ion fluxes across the membrane, 2) binding to a membrane-located steroid hormone or G-protein coupled receptor leading to rapid affects via second messenger systems (Ca, IP3, cyclic AMP and protein kinase C) and, 3) via proteins dissociated after steroid-receptor complex formation (heat shock proteins, proteins of the MAPK signaling system) [22, 45, 46].

While the exact mechanism requires further study, non-genomic signaling may explain the conflicting evidence for estrogen and progesterone effects on asthmatic inflammation. Early menarche is a risk factor for developing asthma [47]. In addition, increased female airway hyperresponsiveness to an inhaled methacholine challenge emerges coincident with secondary sex characteristics [48], suggesting that asthmatic inflammation may be propagated by estrogen. This pro-inflammatory concept is reinforced because adult asthmatic women show more airway hyperresponsiveness to allergic stimuli [49, 50], are more likely to be categorized with severe asthma [51], and have more hospitalizations for asthma than men [52]. However, some studies suggest an anti-inflammatory role of estrogen as exogenous administration of estradiol is associated with improvement in asthma symptoms [53, 54], especially in women with severe premenstrual asthma [53, 55]. With respect to progesterone, administration of exogenous progesterone lessened the premenstrual dips in peak flow of asthmatic women [56] suggesting an anti-inflammatory role. However, progesterone appears to be pro-inflammatory in some mouse models by increasing total immunoglobulin E (IgE) [57], airway eosinophilia, interleukin (IL)-4 and interferon (IFN)-α [58]. The difference in the pro- and anti-inflammatory effects of estrogen and progesterone may be explained by the combined effect of rapid, non-genomic signaling and non-classical signaling on NFκB. Estrogen and progesterone fluctuate frequently during the normal menstrual cycle. Rapid changes in sex hormone concentrations and/or ratios may activate or deactivate kinases leading to altered phosphorylation of NFκB or its inhibitory co-factor, IκB. This may tip the balance of downstream signaling to either a pro- or anti-inflammatory state.

Overlap and interplay of signaling mechanisms in asthma

Either via classical, non-classical signaling, or rapid genomic affects, current data examining glucocorticoids, sex steroid hormones, and 1,25 dihydroxyvitamin D show commonality of downstream signaling pathways, namely through NFκB. We propose that through NFκB, glucocorticoids, estrogen, progesterone, and 1,25 dihydroxyvitamin D work to modulate inflammation. (See figure). In this model, NFκB is a common target for inhibition by glucocorticoids, sex steroid, and secosteroids as studies show that NFκB directly interacts with each of the steroid hormone receptors[59], While this model highlights the known effects of glucocorticoids on asthma, it also integrates the anti-inflammatory evidence of estrogen and 1,25 dihydroxyvitamin D on asthma. This is a novel model because it encompasses a systems biology approach, integrating the simultaneous effects of steroid hormones as would be seen in natural biological systems.

In addition, our model incorporates the variable effects of sex steroid hormones. We propose that estrogen may alter the inflammatory “balance” such that glucocorticoids and estrogen work antagonistically in the asthmatic lung with estrogen increasing inflammation, but its effects are modulated by glucocorticoids, progesterone, and 1,25 dihydroxyvitamin D. The inflammatory balance may be mediated through rapid, non-genomic actions of estrogen. Further, it is the steroid hormone balance between the “pro-inflammatory” estrogen and the “anti-inflammatory” glucocorticoids and progesterone that contributes to the inflammatory process in asthma. Further, we believe that 1,25 dihydroxyvitamin D serves a supporting, but critical role by augmenting the anti-inflammatory actions of glucocorticoids. From a clinical perspective, this refined model incorporating sex steroid hormones and 1,25 dihydroxyvitamin D accurately represents the literature. As mentioned prior, gender differences in airway hyperresponsiveness to allergic stimuli occur when secondary sex characteristics are becoming apparent[48]. It is possible that the introduction of sex hormones serves as a potent inflammatory signal, releasing NFκB from IκB, allowing for the transcription and release of inflammatory signals. Finally, low 1,25 dihydroxyvitamin D levels are associated with increased airway hyperresponsiveness and reduced glucocorticoid response [60]. Increased levels of 1,25 dihydroxyvitamin D, resulting in inhibition of VDR on NFκB may improve asthma symptoms and sensitivity to glucocorticoids.


Asthma is a complex condition whose phenotype is modulated by steroid hormones. Despite our understanding of the impact of individual steroids (e.g. glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be better understanding of the interplay of classical, non-classical, and non-genomic steroid hormone function. However, clues from the conserved homology steroid hormone structure and function and signaling pathways, offer insight into a possible model of steroid hormone regulation of inflammation in asthma through common NFκB-mediated downstream events.


Funding support provided by grant K12HD001399-11 (ASP).


1. Martinez FD. Definition of pediatric asthma and associated risk factors. Pediatr Pulmonol Suppl. 1997;15:9–12. [PubMed]
2. Hollenberg SM, Weinberger C, Ong ES, et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985;318:635–41. [PubMed]
3. Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem. 1996;271:9550–9. [PubMed]
4. Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. 1997;186:1567–74. [PMC free article] [PubMed]
5. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science. 1997;277:1508–10. [PubMed]
6. Richer JK, Jacobsen BM, Manning NG, et al. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem. 2002;277:5209–18. [PubMed]
7. Graham JD, Clarke CL. Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells. Breast Cancer Res. 2002;4:187–90. [PMC free article] [PubMed]
8. Sartorius CA, Melville MY, Hovland AR, et al. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol. 1994;8:1347–60. [PubMed]
9. Sunn KL, Cock TA, Crofts LA, et al. Novel N-terminal variant of human VDR. Mol Endocrinol. 2001;15:1599–609. [PubMed]
10. Pike JW, Meyer MB. The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3) Endocrinol Metab Clin North Am. 39:255–69. table of contents. [PMC free article] [PubMed]
11. Bain DL, Heneghan AF, Connaghan-Jones KD, et al. Nuclear receptor structure: implications for function. Annu Rev Physiol. 2007;69:201–20. [PubMed]
12. Morani A, Warner M, Gustafsson JA. Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. J Intern Med. 2008;264:128–42. [PubMed]
13. Nicolaides NC, Galata Z, Kino T, et al. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 75:1–12. [PMC free article] [PubMed]
14. Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–31. [PubMed]
15. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids. 2005;70:407–17. [PubMed]
16. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol. 2006;102:11–21. [PubMed]
17. Picard D, Yamamoto KR. Two signals mediate hormone-dependent nuclear localization of the glucocorticoid receptor. EMBO J. 1987;6:3333–40. [PubMed]
18. Graupner G, Wills KN, Tzukerman M, et al. Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity. Nature. 1989;340:653–6. [PubMed]
19. Pratt WB, Jolly DJ, Pratt DV, et al. A region in the steroid binding domain determines formation of the non-DNA-binding, 9 S glucocorticoid receptor complex. J Biol Chem. 1988;263:267–73. [PubMed]
20. Webster NJ, Green S, Jin JR, et al. The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell. 1988;54:199–207. [PubMed]
21. Vegeto E, Allan GF, Schrader WT, et al. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell. 1992;69:703–13. [PubMed]
22. Stahn C, Lowenberg M, Hommes DW, et al. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol. 2007;275:71–8. [PubMed]
23. Auphan N, DiDonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995;270:286–90. [PubMed]
24. Hansdottir S, Monick MM, Lovan N, et al. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 184:965–74. [PMC free article] [PubMed]
25. Waterman WR, Xu LL, Tetradis S, et al. Glucocorticoid inhibits the human pro-interleukin lbeta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer. Mol Immunol. 2006;43:773–82. [PubMed]
26. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med. 2003;139:359–70. [PubMed]
27. Freishtat RJ, Watson AM, Benton AS, et al. Asthmatic Airway Epithelium is Intrinsically Inflammatory and Mitotically Dyssynchronous. Am J Respir Cell Mol Biol [PMC free article] [PubMed]
28. Karin M, Yang-Yen HF, Chambard JC, et al. Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. Eur J Clin Pharmacol. 1993;45(Suppl 1):S9–15. discussion S43–4. [PubMed]
29. Jonat C, Rahmsdorf HJ, Park KK, et al. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990;62:1189–204. [PubMed]
30. McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev. 1999;20:435–59. [PubMed]
31. Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol. 2000;74:311–7. [PubMed]
32. Porter W, Saville B, Hoivik D, et al. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol. 1997;11:1569–80. [PubMed]
33. Tseng L, Tang M, Wang Z, et al. Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts. DNA Cell Biol. 2003;22:633–40. [PubMed]
34. Cerillo G, Rees A, Manchanda N, et al. The oestrogen receptor regulates NFkappaB and AP-1 activity in a cell-specific manner. J Steroid Biochem Mol Biol. 1998;67:79–88. [PubMed]
35. Ray P, Ghosh SK, Zhang DH, et al. Repression of interleukin-6 gene expression by 17 beta-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-kappa B by the estrogen receptor. FEBS Lett. 1997;409:79–85. [PubMed]
36. Lu X, Farmer P, Rubin J, et al. Integration of the NfkappaB p65 subunit into the vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1,25-dihydroxyvitamin D3-stimulated transcription. J Cell Biochem. 2004;92:833–48. [PubMed]
37. Chung J, Koyama T, Ohsawa M, et al. 1,25(OH)(2)D(3) blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-kappaB. Lab Invest. 2007;87:540–7. [PubMed]
38. Croxtall JD, Choudhury Q, Flower RJ. Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol. 2000;130:289–98. [PMC free article] [PubMed]
39. Song RX, McPherson RA, Adam L, et al. Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol Endocrinol. 2002;16:116–27. [PubMed]
40. Rosenfeld CR, White RE, Roy T, et al. Calcium-activated potassium channels and nitric oxide coregulate estrogen-induced vasodilation. Am J Physiol Heart Circ Physiol. 2000;279:H319–28. [PubMed]
41. Lange CA. Integration of progesterone receptor action with rapid signaling events in breast cancer models. J Steroid Biochem Mol Biol. 2008;108:203–12. [PMC free article] [PubMed]
42. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8–28. [PubMed]
43. MacLaughlin JA, Cantley LC, Holick MF. 1,25(OH)2D3 increases calcium and phosphatidylinositol metabolism in differentiating cultured human keratinocytes. J Nutr Biochem. 1990;1:81–7. [PubMed]
44. Barsony J, Marx SJ. Rapid accumulation of cyclic GMP near activated vitamin D receptors. Proc Natl Acad Sci U S A. 1991;88:1436–40. [PubMed]
45. Buttgereit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids. 2002;67:529–34. [PubMed]
46. Cato AC, Nestl A, Mink S. Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE. 2002;2002:re9. [PubMed]
47. Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol. 2006;117:1001–7. [PubMed]
48. Tantisira KG, Colvin R, Tonascia J, et al. Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history. Am J Respir Crit Care Med. 2008;178:325–31. [PMC free article] [PubMed]
49. Manfreda J, Sears MR, Becklake MR, et al. Geographic and gender variability in the prevalence of bronchial responsiveness in Canada. Chest. 2004;125:1657–64. [PubMed]
50. Forastiere F, Corbo G, Dell’Orco V, et al. A longitudinal evaluation of bronchial responsiveness to methacholine in children: role of baseline lung function, gender, and change in atopic status. Am J Respir Crit Care Med. 1996;153:1098–1104. [PubMed]
51. The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J. 2003;22:470–477. [PubMed]
52. Chen Y, Stewart P, Johansen H, et al. Sex difference in hospitalization due to asthma in relation to age. Journal of Clinical Epidemiology. 2003;56:180–187. [PubMed]
53. Ensom MH, Chong G, Beaudin B, et al. Estradiol in severe asthma with premenstrual worsening. Ann Pharmacother. 2003;37:1610–3. [PubMed]
54. Chandler MH, Schuldheisz S, Phillips BA, et al. Premenstrual asthma: the effect of estrogen on symptoms, pulmonary function, and beta 2-receptors. Pharmacotherapy. 1997;17:224–34. [PubMed]
55. Matsuo N, Shimoda T, Matsuse H, et al. A case of menstruation-associated asthma: treatment with oral contraceptives. Chest. 1999;116:252–3. [PubMed]
56. Lam SM, Huang SC. Premenstrual asthma: report of a case with hormonal studies. J Microbiol Immunol Infect. 1998;31:197–9. [PubMed]
57. Mitchell VL, Gershwin LJ. Progesterone and environmental tobacco smoke act synergistically to exacerbate the development of allergic asthma in a mouse model. Clin Exp Allergy. 2007;37:276–86. [PubMed]
58. Hellings PW, Vandekerckhove P, Claeys R, et al. Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy. 2003;33:1457–63. [PubMed]
59. McKay LI, Cidlowski JA. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol Endocrinol. 1998;12:45–56. [PubMed]
60. Sutherland ER, Goleva E, Jackson LP, et al. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 181:699–704. [PMC free article] [PubMed]