Rosalyn M. White

Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice

Objective The differential role of the IL-1 agonists, IL-1α, which is mainly cell-associated versus IL-1β, which is mostly secreted, was studied in colon inflammation. Design Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1α or IL-1β, and in wild-type mice, or in mice with conditional deletion of IL-1α in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1α or IL-1β of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. Results IL-1α released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1α deficient mice exhibited mild disease symptoms with improved recovery. IL-1β is involved in repair of IECs and reconstitution of the epithelial barrier during the resolution of colitis; its deficiency correlates with disease exacerbation. Neutralisation of IL-1α in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1β antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. Conclusions The role of IL-1α and IL-1β differs in DSS-induced colitis in that IL-1α, mainly of colon epithelial cells is inflammatory, whereas IL-1β, mainly of myeloid cell origin, promotes healing and repair. Given the dissimilar functions of each IL-1 agonistic molecule, an IL-1 receptor blockade would not be as therapeutically effective as specific neutralising of IL-1α, which leaves IL-1β function intact.

Interleukin-6 release following scorpion sting in children

Interleukin-6 levels were measured in the serum of ten children following severe scorpion envenomation. Measurements were taken on arrival, at the emergency room, and 12 and 24 hr after arrival. Interleukin-6 was markedly elevated in the serum of eight out of ten children on arrival. Interleukin-6 levels gradually decreased toward normal values on 12 and 24 hr measurements, but remained above control levels on all measurements. These results imply that signs and symptoms following scorpion envenomation may in part be explained by release of cytokines. Human and experimental animal studies are required in order to verify the assumption that interleukin-6 and other cytokines are involved in the pathogenesis of scorpion envenomation.

IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice

The role of host-derived IL-1 on the course of Leishmania major infection in susceptible BALB/c mice was assessed. Manifestations of the disease were more severe in mice deficient in the physiological inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra) in comparison with control mice. In mice lacking one of the IL-1 genes (IL-1alpha or IL-1beta), there was delayed development of the disease and more attenuated systemic inflammatory responses. IL-1alpha-deficient mice were slightly more resistant to L. major infection compared with IL-1beta-knockout mice. During disease progression in IL-1Ra KO and control mice, myeloid-derived suppressor cells invaded the spleen, concomitant to suppression of T cell-mediated immunity and expression of systemic high levels of pro-inflammatory cytokines. In IL-1-deficient mice, T(h)1 responses were still apparent, even at late stages of the disease. Thus, dose-dependent effects of IL-1 were shown to influence the pathogenesis of murine leishamaniasis in susceptible BALB/c mice. Physiological and supra-physiological levels of IL-1 in the microenvironment promoted an exacerbated form of disease, whereas sub-physiological doses of IL-1 induced a less progressive disease. Thus, manipulation of IL-1 levels in the host, using the IL-1Ra or specific antibodies, has the potential to alleviate symptoms of visceral manifestations of leishmaniasis.

Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1α

Constitutive expression of cell‐associated, but not secreted, interleukin‐1α (IL‐1α) by oncogene‐transformed fibrosarcoma cells induced regressing tumors in mice, a phenomenon that was abrogated by the IL‐1 inhibitor, the IL‐1 receptor antagonist (IL‐1Ra). On the contrary, non‐IL‐1α‐expressing tumor cells induce progressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL‐1α‐positive fibrosarcoma cells depends on CD8+ T cells, which can also be activated in CD4+ T cell‐depleted mice, with some contribution of natural killer cells. In spleens of mice bearing the non‐IL‐1α‐expressing fibrosarcoma cells, some early and transient manifestations of antitumor‐specific immunity, such as activation of specific proliferating T cells, are evident; however, no development of cytolytic T lymphocytes or other antitumor protective cells could be detected. In spleens of mice bearing the non‐IL‐1α‐expressing fibrosarcoma cells, the development of early tumor‐mediated suppression was observed, and in spleens of mice injected with IL‐1α‐positive fibrosarcoma cells, protective immunity developed in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic‐inactivated, IL‐1α‐positive fibrosarcoma cells, at a critical interval after injection of the malignant cells (Days 5–12), induced tumor regression, possibly by potentiating and amplifying transient antitumor cell immune responses or by ablation of tumor‐mediated suppression. Membrane‐associated IL‐1α may thus serve as an adhesion molecule, which allows efficient cell‐to‐cell interactions between the malignant and immune effector cells that bear IL‐1Rs and function as a focused cytokine with adjuvant activities at nontoxic, low levels of expression. Our results also point to the potential of using antitumor immunotherapeutic approaches using cell‐associated IL‐1α.

Distinct Patterns of IL-Lα and IL-Lβ Organ Distribution-A Possible Basis for Organ Mechanisms of Innate Immunity

The findings presented in this work show that IL-1α and IL-1β display differential and even inverse patterns of organ expression, demonstrated most clearly at old age and beyond the realm of immunology. Based on these IL- 1α /IL- 1β specific patterns of organ expression and considering the distinct physiological function of various organs, IL-1 a may be highlighted more as a potent anti-infectious/toxic agent, which can initiate and potentiate prolonged inflammatory responses, apparently mainly based on activation of cellular immunity. In contrast, it possibly appears that IL-1α may be involved in more restricted inflammatory responses, than conceived before. Other homeostatic functions of both IL-1 molecules can also be envisioned, including for example control of the cell cycle and apoptosis. In this context, diverse and even opposing biological effects of IL-la/IL-lb may be anticipated. The “net” activity of IL-1 in a certain organ may depend on the type of expressed IL-1 and IL-lreceptors, as well as on the locally operant cytokine network. The in vivo interactions between the two IL-1 forms may be of crucial importance to organ homeostasis, especially under the stressful conditions, characterizing old age. Further studies are needed to clarify the full perspective of IL-la and IL-lb roles in organ homeostasis, the understanding and manipulation of which may hopefully lead to development of beneficial therapeutic interventions.

Effects of IL-1 molecules on growth patterns of 3-MCA-induced cell lines: An interplay between immunogenicity and invasive potential

The balance between inflammation and immunity is cardinal for the outcome of the malignant process. Local attenuated inflammatory responses mediated by innate cells may provide accessory signals for the development of acquired immunity against malignant cells. In contrast, excessive inflammatory responses accompany tumorigenesis and tumor invasiveness, by the induction of immunosuppression. In the present study, we have assessed the role of tumor cell-derived IL-1 in determining the invasive versus immunostimulatory potential of tumor cells. For this purpose, we have used 3-MCA-induced fibrosarcoma cell lines from IL-1 knockout (KO) versus control mice. Cell lines with no IL-1 failed to establish tumors in intact mice, while lines obtained from control mice were invasive and induced a potent angiogenic response. In contrast, cell lines from IL-1KO mice were more immunogenic. SDF-1 and IL-6, each induced by IL-1, were the two major cytokines whose levels differed in cell lines with or without IL-1. We could not detect differences in cell surface markers related to immunogenicity, such as MHC Class I, co-stimulatory, or adhesion molecules between both types of cells. However, more T-cells were observed at the inoculation site of tumor cells devoid of IL-1 and more pronounced parameters related to anti-tumor immunity were observed in the spleen (IL-12 and IFNγ) of these mice, compared to mice bearing tumors derived from control mice, where host-derived IL-1 is present. In addition, injection of tumor cells devoid of IL-1, which failed to grow in mice, induced an anti-tumor cell immune memory, while in mice injected with tumor cells from control mice; no immune memory could be detected. From the results, it seems that IL-1 is a crucial factor in determining the balance between immunity and inflammation in tumor-bearing mice. This suggests that manipulation of IL-1 could be useful in anti-tumor therapy, by reducing invasiveness and promoting immunity against the malignant cells.