Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Signal transduction through IL c

    2019-11-01

    Signal transduction through IL-34/ c-FMS ligand receptor also leads to the differentiation, survival and, angiogenesis, proliferation, adhesion and migration of cells of the monocyte/macrophage lineage similar to that of CSF-1 through the various pathways-First is through FAK (Focal Adhesion Kinase) phosphorylation, secondly through Ras/Raf.MEK/ERK signalling path, thirdly through the STAT3 phorphorylation and fourthly through PI3K, PDK1 and AKT [36] (Fig. 2.6 ).
    Applications of CSF-1R/c-FMS inhibitors in various therapeutic implications
    Compounds exhibiting c-FMS inhibitory activity
    c-FMS/CSF-1R inhibitors under clinical investigations
    Conclusion
    Introduction Macrophage colony-stimulating factor (CSF-1) controls the proliferation and differentiation of cells of the mononuclear phagocyte lineage [1], [2], [3]. The receptor for CSF-1 (CSF-1R, MCSFR, CD115 or FMS) is expressed in all cells of the mononuclear phagocyte lineage including progenitor cells, osteoclasts and dendritic cells [4]. CSF-1R is the proto-oncogene form of the transforming gene of Feline McDonough Sarcoma (SM-FeSV), hence its name FMS [5]. A second ligand for the CSF-1R was first described in humans [6] and subsequent studies confirmed that the two-ligand, one-receptor, system is conserved in ACSF mg [7]. Binding of either ligand to the CSF-1R produces receptor dimerization, auto-phosphorylation, activation of down-stream signalling (ERK1/2, Akt) and expression of genes involved in survival and proliferation of the mononuclear phagocyte lineage cells [6], [8], [9], [10]. Human CSF-1 cDNA was cloned and expressed in the 1980s, and when injected into mice, it promoted an increase in blood monocyte and tissue macrophage numbers [11]. Human CSF-1 is almost as effective as mouse CSF-1 in stimulating mouse macrophage proliferation in vitro [12], [13] and indeed is equally active on all mammalian species tested (mouse, cat, sheep, dog, and pig). Conversely, mouse CSF-1 bioactivity is restricted to non-primate species [2], [7], [14], [15], [16], [17], [18]. IL-34 has even more restricted species cross-reactivity; with the human and mouse ligands much less active on the other species, although both were active on the pig CSF-1R [2]. CSF-1 has been widely-used to drive proliferation and differentiation of mature macrophages from bone marrow or blood monocyte progenitors in multiple species. In general, CSF-1 stimulated cells are driven towards a more immunosuppressive function [1], [19], where another colony-stimulating factor, GM-CSF or CSF-2, drives differentiation of phagocytic cells with antigen-presenting function [20], [21]. GM-CSF has been used to produce antigen presenting cells (APCs) from feline bone marrow [22], [23], [24], but there are no reports of using CSF-1 to generate feline monocyte derived macrophages. Recombinant colony stimulating factors and/or antibodies directed against the ligand or the receptor have been tested in a range of animal models and human patients [1], [25], [26], [27]. Macrophages play an important role in tissue repair in a number of tissues including kidney, liver, heart, brain and lung [28], [29], [30], [31], [32] and CSF-1 administration has been shown to promote regeneration in a number of models. For example, in ischaemia reperfusion in mice, a model of acute renal injury, recombinant human CSF-1 administration was able to stimulate macrophage infiltration to promote epithelial repair and to prevent interstitial fibrosis [33]. Acute renal failure in cats can arise from numerous causes [34], [35], [36], [37], [38], [39], [40] and has a very poor prognosis [36], [41]. Many cats who survive to discharge are azotaemic and, as a result, are likely to have high morbidity and greatly-reduced lifespan, while a second “wave” of apoptosis seems to occur in the recovery phase which may limit further regeneration [42]. The studies in the mouse model suggest that CSF-1 could have a therapeutic benefit in cats with acute renal injury. For this purpose, we need to know whether it would be necessary to produce feline-specific agents. In the present study, we have produced a cat CSF-1R-expressing factor-dependent cell line and evaluated responsiveness of the cat receptor to CSF-1 and IL-34 from multiple species.