Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching

Jabara, Haifa H.; Brodeur, Scott R.; Geha, Raif S.

doi:10.1172/jci10168

Cited by 68 publications

(51 citation statements)

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“…IL-4-dependent IgE responses to CD40 crosslinking and HC typically follow similar profiles (46,65), which is consistent with the notion that HC induces IgE synthesis by upregulating CD40 ligand expression on T cells, thus promoting crosslinking of CD40 on the B cell membrane (46). Our experiments unveiled novel aspects of the interaction between IL-13 and the B cell-activating signals required for IgE switching.…”

Section: Discussionsupporting

confidence: 84%

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IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

et al. 2005

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Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13Rα2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.

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Section: Discussionsupporting

confidence: 84%

“…45). Hydrocortisone (HC) has also been shown to potently synergize with IL-4 in inducing IgE synthesis, largely through its ability to upregulate CD40 ligand expression in T and possibly B cells (46). The interactions between HC and IL-13 have not been investigated.…”

Section: Figurementioning

confidence: 99%

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

et al. 2005

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“…Monocyte chemoattractant protein (MCP)-1, MCP-3, MCP-4, and eotaxin chemokine synthesis. [11][12][13] Also, glucocorticoids inhibit immunoglobulin G (IgG), IgM, and IgA antibody synthesis, 14 phospholipase A2 enzyme (cPLA2) expression, and production of leukotrienes 15 and prostaglandins. 16 As a consequence, there is reduced neutrophil, eosinophil, and macrophage recruitment to the inflammatory site, impaired cell differentiation and survival, 8,17 decreased nitric oxide (NO) production, reduced expression of the adhesion costimulatory and major histocompatibility complex (MHC) molecules, 16,18,19 lowered pulmonary mucous secretion, 19 and impaired apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone Effects in the Strongyloides venezuelensis Infection in A Murine Model

Machado¹,

Carlos²,

Sorgi³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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The aim of this study was to investigate the immunomodulatory effects of glucocorticoids on the immune response to Strongyloides venezuelensis in mice. Balb/c mice were infected with S. venezuelensis and treated with Dexamethasone (Dexa) or vehicle. Dexa treatment increased circulating blood neutrophil numbers and inhibited eosinophil and mononuclear cell accumulation in the blood, bronchoalveolar, and peritoneal fluid compared with control animals. Moreover, Dexa decreased tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-3 (IL-3), IL-4, IL-5, IL-10, and IL-12 production in the lungs and circulating immunoglobulin G1 (IgG1), IgG2a, and IgE antibody levels while increasing the overall parasite burden in the feces and intestine. Dexa treatment enhanced the fertility of female nematodes relative to untreated and infected mice. In summary, the alterations in the immune response induced by Dexa resulted in a blunted, aberrant immune response associated with increased parasite burden. This phenomenon is similar to that observed in S. stercoralis-infected humans who are taking immunosuppressive or antiinflammatory drugs, including corticosteroids.

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“…This can now be understood, as the high doses of systemic corticosteroid therapy may maintain high IgE levels by the mechanisms described by Jabara and colleagues (10). This effect can be overcome by anti-IgE therapy, which appears to be of greater benefit in patients with more severe disease who are steroid dependent.…”

Section: Clinical Outlookmentioning

confidence: 97%

“…Such individuals have low levels of secreted immunoglobulins, and they fail to induce IgE synthesis in response to corticosteroids. Similarly, as Jabara et al report, a blocking CD40-Ig fusion protein inhibits the effects of hydrocortisone on IgE synthesis in normal B cells (10). The effect of corticosteroids on CD40L is mediated by GR, as it is blocked by the GR antagonist mifepristone (RU486).…”

mentioning

confidence: 90%

Corticosteroids, IgE, and atopy

Barnes¹

2001

J. Clin. Invest.

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Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching

Cited by 68 publications

References 50 publications

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Dexamethasone Effects in the Strongyloides venezuelensis Infection in A Murine Model

Corticosteroids, IgE, and atopy

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