Neopterin, a compound derived from GTP, represents a precursor molecule of biopterin that is an essential cofactor in neurotransmitter synthesis. We have recently reported that in vivo as well as in vitro immune responses are accompanied by an increased release of neopterin and that this phenomenon can be used for the biochemical monitoring of diseases accompanied by hyperimmune stimulation. This article deals with the cellular origin and the control of this immune response-associated neopterin release in vitro. Using highly purified or monoclonal cellular reagents we demonstrate that macrophages (M phi) stimulated with supernatants from activated T cells release large amounts of neopterin into culture supernatants. Further experiments involving induction of neopterin release from M phi with various human recombinant interferons (IFNs) or neutralization of the effect of T cell supernatants with various monoclonal anti-IFN antibodies revealed immune IFN as the active principle. It thus appears that a metabolic pathway so far exclusively known in context with the generation of an essential cofactor of neurotransmitter-synthesis during immune responses is also activated in M phi under stringent control by immune IFN-like lymphokines.

Molecular cloning and biochemical studies identified protein kinase C (PKC) enzymes as members of a distinct family of serine/threonine protein kinases, playing critical roles in the regulation of cellular differentiation and proliferation of diverse cell types (reviewed in reference 36). In an attempt to find PKC isoforms that are involved in growth control and/or activation of T lymphocytes, we have identified PKC-(5), whose human gene locus was recently mapped to chromosome 10p15 (15). PKC-is characterized by a unique tissue distribution, i.e., in skeletal muscle, lymphoid organs, and hematopoietic cell lines, particularly T cells (4,5,10,34,39,53), and by isoenzyme-specific activation requirements and substrate preferences in vitro (4). PKC-undergoes cytosol-to-membrane translocation in T cells stimulated with phorbol esters (4), implying that this isoform is likely to be involved in T-cell activation pathways. The unique expression and functional properties of PKC-suggest that it may play a specialized role in T-cell signaling pathways.T-cell activation results in the expression of interleukin-2 (IL-2), an autocrine growth factor that is a critical stimulus for the growth and differentiation of B and T lymphocytes. Pharmacological and biochemical studies indicate that activation of two major signaling pathways, one of which can be triggered by phorbol esters (such as phorbol 12-myristate 13-acetate [PMA]) and the other of which can be triggered by Ca 2ϩ ionophores, is required for induction of IL-2 (reviewed in reference 51). A substantial amount of work over the past several years has shown the requirement of cooperative interactions of several transcription factors, including AP-1, NF-B, NF-AT, and NF-IL2A (Oct-1), with the minimal inducible promoter/enhancer region of the IL-2 gene (11). Several lines of evidence point to AP-1 as a critical transcription factor for IL-2 regulation. AP-1 is a dimer of different members of the Fos (c-Fos, FosB, Fra-1, Fra-2, and FosB2) and Jun (c-Jun, JunB, and JunD) family of proteins (1). AP-1 thereby interacts with the IL-2 regulatory region directly (25,26,33,47) and also indirectly as a component of NF-AT and NF-IL2 (37, 50). AP-1 activity is regulated by de novo synthesis of Jun and Fos proteins, as well as by posttranslational modifications such as phosphorylation and dephosphorylation (1,8,9,30,43,48). Two potential AP-1-binding sites have been identified in the mouse and human IL-2 enhancer region at Ϫ150 bp (proximal AP-1) and Ϫ180 bp (distal AP-1). These elements show sequence similarity to the consensus AP-1 enhancer sequence and have been studied by deletional, mutational, and gel shift analyses (14,18,25,40). Most of these data support an important role for AP-1 in IL-2 transcription, especially as a result of the interaction with the proximal enhancer site (25).PKC has been implicated in the activation of AP-1 in T lymphocytes, as demonstrated by studies involving PKC-specific pharmacological inhibitors (24, 28) or PKC down-regulation by chronic phorbol este...

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