The Role of Interleukin-23 in the Early Development of Emphysema in HIV1⁺Smokers

Abstract

Rationale. Matrix metalloproteinase-9 (MMP-9) expression is upregulated in alveolar macrophages (AM) of HIV1+ smokers who develop emphysema. Knowing that lung epithelial lining fluid (ELF) of HIV1+ smokers contains increased levels of inflammatory cytokines compared to HIV1− smokers, we hypothesized that upregulation of lung cytokines in HIV1+ smokers may be functionally related to increased MMP-9 expression. Methods. Cytokine arrays evaluated cytokine protein levels in ELF obtained from 5 groups of individuals: HIV1− healthy nonsmokers, HIV1− healthy smokers, HIV1− smokers with low diffusing capacity (DLCO), HIV1+ nonsmokers, and HIV1+ smokers with low DLCO. Results. Increased levels of the Th17 related cytokine IL-23 were found in HIV1− smokers with low DLCO and HIV1+ smokers and nonsmokers. Relative IL-23 gene expression was increased in AM of HIV1+ individuals, with greater expression in AM of HIV1+ smokers with low DLCO. Infection with HIV1 in vitro induced IL-23 expression in normal AM. IL-23 stimulation of AM/lymphocyte cocultures in vitro induced upregulation of MMP-9. Lung T lymphocytes express receptor IL-23R and interact with AM in order to upregulate MMP-9. Conclusion. This mechanism may contribute to the increased tissue destruction in the lungs of HIV1+ smokers and suggests that Th17 related inflammation may play a role.

HIV induces airway basal progenitor cells to adopt an inflammatory phenotype

“…Total RNA and culture supernatants were analyzed for cytokine gene expression and release. We focused on GM-CSF, IL-8, IL-1β and ICAM-1 as these mediators are relevant to COPD pathogenesis and are found at increased levels in epithelial lining fluid from HIV + individuals 35 , 63 and HIV + BC-conditioned media when cells were cultured ex vivo (Fig. 1 A).…”

“…Nonadherent cells were removed by thorough washing with RPMI 1640. AM represented ≥ 95% of cells 47 , 61 – 63 .…”

Immunoregulatory Functions of the IL-12 Family of Cytokines in Antiviral Systems

“…Similarly, in order to inhibit IFN-γ production, IL-23 can promote SOCS1 production in T cells [28]. In vitro, the expansion of IL-23 can mediate the cooperation of T lymphocytes and alveolar macrophages (AM) to stimulate IL-23R expression in HIV-1+ smokers [29] (Table 1). In HCV infections, with the increase in IL-23, IL-17A as well as IFN-γ induced by peripheral blood mononuclear cells (PBMCs) increases while the number of PBMCs producing IL-21 decreases through the regulation of Th17 [30].…”

Mechanisms Underlying HIV-Associated Noninfectious Lung Disease

“…Infection of AMs results in expression of IL-23, which can lead to upregulation of MMP-9 in AMs in an AM/lymphocyte coculture model. 13 Studies of human macrophages have consistently located MMP-12 and MMP-9 in emphysematous lung. 71 Murine models have demonstrated that macrophage overexpression of MMP-9 or MMP-1 can spontaneously induce emphysema, while MMP-12 knockdown is protective from cigarette smoke-induced emphysema.…”

“…This inflammation leads to the expression of inflammatory cytokines and release of matrix metalloproteinases associated with COPD. 12,13 HIV infection…”