Differences in cytokine secretion by intestinal mononuclear cells, peripheral blood monocytes and alveolar macrophages from HIV-infected patients

Abstract

SUMMARY Mononuclear cells of the lamina propria (LpMNC), isolated from endoscopically taken biopsies of the large bowel from AIDS patients, were analysed for their ability to secrete tumour necrosis factor‐alpha (TNF‐α), IL‐lβ and IL‐6. Stimulation of LpMNC from normal controls with pokeweed mitogen (PWM) led to a time‐ and dose‐dependent enhancement of TNF‐α, IL‐1β and IL‐6 secretion. In contrast, PWM stimulation of LpMNC from AIDS patients resulted in only a small increase in TNF‐a release. Constitutive secretion of IL‐1β and IL‐6 in these patients was already increased to the concentration range of stimulated cells from normal controls and could not be further increased, probably due to maximal in vivo stimulation. Secretion of TNF‐α, IL‐1β and IL‐6 by peripheral blood monocytes (PBM) and alveolar macrophages from AIDS patients was elevated with or without stimulation compared with normal controls. Obviously, the regulation of TNF‐α secretion is dependent on the microenvironment. Since it is known that interferon‐gamma (IFN‐γ) may induce the production of TNF‐α, the secretion of this cytokine was examined. Release of IFN‐γ was constitutively and under stimulation lowered in LpMNC from AIDS patients compared with normal controls. Addition of IFN‐γ to LpMNC did not result in enhanced TNF‐α secretion. Our data indicate a defective function of intestinal mononuclear cells in AIDS patients as shown by the diminished TNF‐α secretion.

Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients

“…However, conflicting results were reported as to whether or not inflammatory cytokines are actually increased in the intestinal mucosa of untreated HIV-infected patients. Based on tissue RNA quantification, increased mucosal cytokine expression has been described,52 – 56 but mononuclear cells isolated from the colon of HIV-infected patients did not show increased production of cytokines 57 58. In contrast to the latter findings, we found increased mucosal production of TNFα, IL2 and IL4 in our untreated HIV-infected patients.…”

“…In contrast to the latter findings, we found increased mucosal production of TNFα, IL2 and IL4 in our untreated HIV-infected patients. As we quantified cytokine secretion from intact mucosal biopsies, the failure of isolated mononuclear cells to produce increased amounts of cytokines57 58 may be explained by a lack of co-stimulation “physiologically” provided by the mucosal microenvironment. Finally, a cocktail of the cytokines suspected to cause the barrier defect according to our data evoked a significant barrier defect in rat jejunal mucosa, further corroborating the link between raised inflammatory cytokines and mucosal barrier impairment.…”

HIV induces airway basal progenitor cells to adopt an inflammatory phenotype

“…Increased levels of IL-8 have been found in bronchoalveolar lavage from HIV-infected nonsmokers and HIV + subjects with P. carinii pneumonia 35 , 63 , 85 . AM from HIV + individuals spontaneously release more GM-CSF and IL-8 than those from normal controls 30 , 80 , and there is an increased secretion of IL-1β from AM of HIV + individuals as compared to normals 82 , 100 , 101 . Similar to our observations, X4 tropic HIV enhance the expression of ICAM-1 in in vitro differentiated airway epithelium 38 .…”

Exposure to HIV-1 Directly Impairs Mucosal Epithelial Barrier Integrity Allowing Microbial Translocation

“…The prevailing opinion from these studies is that the effect on epithelial barrier is likely mediated via immune cell activation due to viral replication [14],[25]. Of note are other studies that were unable to show that mononuclear cells isolated from colon of infected patients produce increased amount of cytokines [35],[36]. Thus far the cellular source of inflammatory cytokines that could lead to barrier disruption in HIV infected patients remains controversial [20].…”