Monique A. Berman

Expression of cytokines by multipotent neural progenitor cells

Recent work with mammalian neural stem cells has highlighted the role of cytokine signaling in the proliferation and differentiation of these multipotent cells. While the responsiveness of neural progenitors to exogenously applied growth factors has been demonstrated in vivo as well as in vitro, little attention has been given to the production of cytokines by these cells. Here we use immunocytochemistry, RT-PCR, and ELISA to show that under standard growth conditions multipotent neural progenitor cells from humans express multiple cytokines including IL-1alpha, IL-1beta, IL-6, TGF-beta1, TGF-beta2, TNF-alpha, but not IL-2, IL-4, or IFN-gamma. Neural progenitor cells from rat and mouse express some, but not all, of these cytokines under similar conditions. While the function of cytokine expression by neural progenitor cells remains to be elucidated, these signaling molecules are known to be involved in neural development and may play a role in the activation of quiescent stem cells by a variety of pathological processes.

Cytokine Profiles of Pediatric Patients Treated with Antibiotics for Pyelonephritis: Potential Therapeutic Impact

ABSTRACT Urinary tract infections are common in infants and children. Pyelonephritis may result in serious complications, such as renal scarring, hypertension, and renal failure. Identification of the timing of release of inflammatory cytokines in relation to pyelonephritis and its treatment is essential for designing interventions that would minimize tissue damage. To this end, we measured urinary cytokine concentrations of interleukin-1β (IL-1β), IL-6, and IL-8 in infants and children with pyelonephritis and in healthy children. Children that presented to our institution with presumed urinary tract infection were given the diagnosis of pyelonephritis if they had a positive urine culture, pyuria, and one or more of the following indicators of systemic involvement: fever, elevated peripheral white blood cell count, or elevated C-reactive protein. Urine samples were obtained at the time of presentation prior to the administration of antibiotics, immediately after completion of the first dose of antibiotics, and at follow up 12 to 24 h after presentation. IL-1β, IL-6, and IL-8 concentrations were measured by enzyme-linked immunosorbent assay. Creatinine concentrations were also determined, and cytokine/creatinine ratios were calculated to standardize samples. Differences between preantibiotic and follow-up cytokine/creatinine ratios were significant for IL-1β, IL-6, and IL-8 (P < 0.01). Differences between preantibiotic and control cytokine/creatinine ratios were also significant for IL-1β, IL-6, and IL-8 (P < 0.01). Our study revealed that the urinary tract cytokine response to infection is intense but dissipates shortly after the initiation of antibiotic treatment. This suggests that renal damage due to inflammation begins early in infection, underscoring the need for rapid diagnosis and intervention.

Lymphocyte Recruitment Following Spinal Cord Injury in Mice is Altered by Prior Viral Exposure

The inflammatory response induced by mechanical lesion of the spinal cord is known to include the recruitment of neutrophils and macrophages, while the involvement of lymphocytes has been largely ignored. We have studied the pattern of lymphocyte recruitment following partial transection of the mouse spinal cord. Using immunohistochemical techniques, all three types of lymphocytes (CD4‐positive T‐cells, CD8‐ positive T‐cells and B‐cells) were found in the vicinity of the lesion site within hours and persisted for up to 7 days. There was a predominance of B‐lymphocytes during the first 3 days. A second, late phase of cell infiltration, dominated by CD8‐positive T‐lymphocytes, occurred in mice that had been raised in a conventional breeding unit and had acquired antibody titres to a common murine virus (mouse hepatitis virus). In contrast, mice kept in specific pathogen‐free facilities did not show this late‐phase response. These findings suggest a possible role for lymphocytes in secondary tissue loss, local demyelination, scar formation, cytokine‐mediated inflammatory responses or trophic processes. They also provide evidence that a virus infection can significantly enhance the reaction of T‐cells to a spinal cord lesion.

The immunological properties of adult hippocampal progenitor cells

Adult hippocampal progenitor cells (AHPCs) derived from mature rats were studied in mixed co-cultures and shown not to elicit a proliferative response from human peripheral blood mononuclear cells (PBMCs) or allogeneic spleen cells. FACS analysis revealed low class I and no detectable class II (Ia) MHC expression by these cells. RT-PCR showed that AHPCs express the anti-inflammatory cytokine TGF-beta1. AHPCs did not, however, significantly impede the proliferation of OKT3- or PHA-stimulated PBMCs. Taken together, these results indicate that AHPCs are non-immunogenic in vitro. This is consistent with their pattern of MHC expression and does not require an active immunosuppressive mechanism.

Modulation of IL-1 alpha, IL-1 beta, and 25K Mr non-IL-1 activity released by human mononuclear cells.

To determine if the release of IL‐1α and IL‐1β by cultured PBMC could be independently modulated by different exogenous stimuli, we examined the effect of LPS, IFNγ, latex beads, and indomethacin on the release of IL‐1α and IL‐1β. PBMC culture supernatants were fractionated by Sephacryl‐S‐200 column chromatography or HPLC (TSK G3000SW), and each fraction was tested for thymocyte mitogenic activity in the presence or absence of preincubation with anti‐IL‐1α or anti IL‐1β monoclonal antibody (mAb) and for the presence of IL‐1α or IL‐1β protein by ELISA. In all experiments, thymocyte mitogenic activity not neutralizable by anti‐IL‐1α or anti‐IL‐1β mAb was detected in the 25K Mr range, which ranged from 12 to 50% of the total thymocyte mitogenic activity released, depending on the stimuli. Cultured PBMC from 95% of individuals release thymocyte mitogenic activity in the absence of exogenous stimuli, which was increased 1.3‐ to 7‐fold by lipopolysaccharide (LPS) (25–50 üg/ml). All of this increased activity was due to increased release of IL‐1β and non‐IL‐1 thymocyte mitogenic activity, with no change in the total amount of IL‐1α released. Indomethacin (0.1 μg/ml) induced release of increased thymocyte mitogenic activity of 1.3‐ to 1.4‐fold over unstimulated cultures. All of this increased activity was due to increased release of IL‐1α and non‐IL‐1 activity with a concomitant decrease in IL‐1β release. Interferonγ (40–100 U/ml) increased the amount of IL‐1α and decreased IL‐1β and non‐IL‐1 activity released, resulting in no overall change in the total amount of thymocyte mitogenic activity.