Intercellular communication within the neural and immune systems frequently involves cell type-specific responses to common signalling proteins such as cytokines. The cytokine, Interleukin 4 (IL-4), can be produced by T lymphocytes and by non-T cells within the central nervous system (CNS). Unlike many cytokines that stimulate astrocyte growth, our data indicate that IL-4 inhibits DNA synthesis and proliferation in human, non-neoplastic astrocytes derived from adult cortex. Cell lines derived from low grade astrocytic tumors (astrocytomas) are also inhibited by IL- 4, but lines from highly malignant astrocytomas (glioblastoma multiforme) are refractory to IL-4 despite expression of IL-4 receptors. Based upon our findings we hypothesize that IL-4 represents an anti-mitogenic, differentiating signal in normal astrocytes - a property which is lost in malignant astrocytes. The overall goal of this proposal is to characterize mechanisms of IL-4-mediated growth regulation in human astrocytes, utilizing as a model system, IL-4 responsive and non- responsive human astrocytic cell lines derived, respectively, from low grade astrocytoma and glioblastoma multiforme.
Specific Aims are to: (1) Determine the relationship of IL-4 receptor expression to proliferation in astrocytes. (Are IL-4 receptors modified by mitogenic {EGF} or non-mitogenic {IL-4} signals? Conversely, does IL-4 modify heterologous receptors for mitogenic {EGF} ligands?) (2) Identify mechanisms of IL-4-mediated inhibition of DNA synthesis and proliferation. (Are cell cycle components such as G1/S phase cyclins {Cyclins E and D1} and/or associated cyclin-dependent protein kinases, {cdk2 and cdk4} affected by IL-4? (3) Ascertain the physiological relevance of IL-4 receptor expression to astrocyte proliferation in vivo. (Are IL-4 receptors differentially expressed {by RT-PCR analysis} in tissues characterized by reactive vs. quiescent non-neoplastic astrocytes, or low grade astrocytoma vs glioblastoma multiforme?) Elucidation of processes involved in governing normal adult human astrocyte proliferation could potentially highlight new areas for therapeutic intervention in neoplastic or non-neoplastic diseases of the CNS.
