Hematopoietic, immunomodulatory and epithelial effects of interleukin-11

Abstract

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-kappaB). The block to NF-kappaB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-kappaB, IkappaB-alpha and IkappaB-beta. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFN gamma induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN gamma production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF alpha, IFN gamma and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated...

Chlamydial infection of polarized HeLa cells induces PMN chemotaxis but the cytokine profile varies between disseminating and non-disseminating strains

“…IL-11 production induced by viral or bacterial infections has been reported recently (Elias et al, 1994;Kernacki et al, 1998). IL-11 is a pleiotropic cytokine that exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, arthritis, inflammatory skin disease and various infection±endotoxaemia syndromes (reviewed by Barton et al, 1996;Schwertschlag et al, 1999). The anti-inflammatory properties of IL-11 involve a direct activity on macrophages, independent of other anti-inflammatory mediators, such as IL-10 and TGF-b1 (Trepicchio et al, 1996).…”

“…In addition to effects on macrophages, rhIL-11 also reduces CD4 1 T production of Th1 cytokines, such as interferon (IFN)g induced by IL-12, while enhancing Th2 cytokine production (Schwertschlag et al, 1999). Further, in a murine model of endotoxaemia, rhIL-11 blocked LPSinduced elevation of IFNg serum levels (Trepicchio et al, 1996).…”

Immune restoration following hematopoietic stem cell transplantation: an evolving target

“…For example, IL-11 is an important growth factor for thrombopoiesis. 211 Furthermore, IL-11 has been shown to reduce GVHD in allogeneic murine models. 212 Therefore, IL-11 could be potentially used to stimulate platelet recovery, while decreasing the incidence of GVHD in the HSCT recipient.…”

Interleukin-11 Signals through the Formation of a Hexameric Receptor Complex

“…Recombinant human IL-11 is now used for the treatment of chemotherapy-induced thrombocytopenia (3). IL-11 also has clinical potential for the treatment of several disorders including chemotherapy induced oral mucositis (4), Crohn's disease (5), and rheumatoid arthritis (6).…”