Reduced production of interleukin 12 by interferon gamma primed alveolar macrophages from atopic asthmatic subjects

Abstract

Background-Asthma is characterised pathologically by an inflammatory pulmonary infiltrate rich in T helper (Th) 2 cells and eosinophils. Interleukin (IL)-12 is a heterodimeric cytokine critical for driving the development of uncommitted Th cells to express a Th 1 phenotype. Reduced pulmonary production of IL-12 may therefore play a role in the pathogenesis of asthma by contributing to the pulmonary cytokine imbalance seen in asthma. Methods-IL-12 p70 protein levels in bronchoalveolar lavage fluid and p70 protein levels and IL-12 messenger RNA in alveolar macrophage cultures from normal and atopic asthmatic subjects were measured. Results-There was a significant diVerence between the mean IL-12 p70 protein level in the bronchoalveolar lavage fluid from asthmatic subjects (37.5 pg/ml) and from normal subjects (131 pg/ml, p = 0.04). Alveolar macrophages from asthmatic subjects produced significantly less IL-12 protein (30 pg/ml) and messenger RNA than those from normal subjects (69.5 pg/ml, p<0.005). These diVerences were not caused by inhibition of IL-12 production by IL-10 nor to generalised hyporesponsiveness of asthmatic alveolar macrophages from subjects to the eVects of interferon (IFN)-. Conclusions-Pulmonary IL-12 production is lower in asthmatic subjects. This reduction is not the result of generalised hyporesponsiveness to IFN-. Reduced IL-12 levels may contribute to the development of asthmatic pulmonary inflammation through dysregulation of Th cell development. (Thorax 2000;55:842-847)

Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma

“…It follows that the risk alleles of the IRF5 gene polymorphisms for asthma are related to lower IRF5 expression, whereas those risk alleles for autoimmune disorders linked to a greater IRF5 expression level appear protective for asthma, especially when considering the joint effects of these alleles (haplotype H1). Interestingly, a diminished level of IL-10 and IL-12 has been reported in patients with asthma (Borish et al, 1996;Message et al, 2008;Plummeridge et al, 2000). As IL-10 and IL-12 are directly regulated by IRF5, these observations corroborate our hypothesis that lower IRF5 expression is a risk factor for asthma.…”

Secreted Phospholipase A2Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

“…The increase in sPLA 2 -X in bronchial macrophages in subjects with asthma is important because bronchial macrophages are the most prevalent cell in the airways of patients with asthma under most circumstances, and there are phenotypic alterations in bronchial macrophages in asthma (46,47). In rodent models, bronchial macrophages are important in the development of BHR in response to allergen sensitization (48).…”

Macrophages – Balancing Tolerance and Immunity

“…According to the paradigm, impairment of IL-12 [366][367][368], IL-18 [369], IL-18R [370][371][372] or other Th1-directing signal (such as Myd88) [373,374], variations in inherent T cell-responsiveness [375], or aberrant DC responses to the prevailing microenvironment are all possible mechanisms through which proinflammatory macrophages could drive Th2/Treg responses [63, 376,377]. Speculatively, for example, DCs could be disproportionately responsive to PGE 2 [378][379][380], a product of LPS-stimulated proinflammatory macrophages [381,382], but with welldocumented receptor-mediated antiinflammatory signaling properties.…”