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Chronic inflammatory responses in the lung rely on the continual recruitment of leukocytes to the site of inflammation. Recent data have demonstrated a possible role for stromal cell-derived chemokines in leukocyte recruitment. In the present study we examined the production of interleukin (IL)-8 and ENA-78, members of the C-X-C family of chemokines, and macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, members of the C-C chemokine family, from pulmonary smooth muscle and endothelial cells. The production of IL-8 and ENA-78 was induced by early response cytokines, IL-1 and tumor necrosis factor (TNF), but not by immune-associated cytokines, IL-4, IL-10, or interferon (IFN)-gamma. In contrast, the production of MIP-1 alpha and MIP-1 beta by pulmonary vascular smooth muscle cells increased when stimulated by immune-associated cytokines as well as with IL-1 beta and TNF. The level of MIP-1 alpha production induced in smooth muscle cells by the immune-associated cytokines, IL-4, IFN-gamma, and IL-10 ranged from 0 to 340 pg/ml. The production of MIP-1 beta in response to the immune-associated cytokines IL-4, IFN-gamma, and IL-10 in smooth muscle cells ranged from 260 to 940 pg/ml. Human pulmonary artery endothelial cells did not generate MIP-1 alpha or MIP-1 beta in response to graded doses of any of the cytokines. These data demonstrate differential induction of C-X-C and C-C chemokines from nonimmune stromal cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies have shown that CC chemokines act on monocytes, lymphocytes, eosinophils and basophils, but not neutrophils, with distinct target cell selectivities, possibly explaining the selective attraction and activation of these cell types in different types of chronic inflammation and allergic disease. Functional and desensitization studies on basophils and eosinophils indicate the expression of at least three distinct G-protein-coupled CC chemokine receptors (three on basophils and two on eosinophils), which exert partially selective and partially overlapping ligand specificities and also appear to mediate distinct functions despite similar signal transduction pathways. Functional studies with all known six human CC chemokines show that each cytokine has a distinct spectrum of bioactivities and target cell profile. Interestingly, overall sequence homologies between the chemokines are not predictive for the cell function or cell type that a particular chemokine will preferentially activate, and thus discrete sequence motifs may be important for activating the different CC chemokine receptors. Using different chemokine mutants and hybrids between chemokines, the functional importance of selected individual amino acids and short motifs are now being analysed. These structure-function studies could also lead to antagonists that have more disease-selective anti-inflammatory properties than currently available drugs.

Central nervous system (CNS) involvement is common during human immunodeficiency virus type-1 (HIV-1) infection. The neurologic disease of the CNS most frequently observed during acquired immunodeficiency syndrome (AIDS) is HIV-1-associated cognitive/motor complex or AIDS dementia complex (ADC), which is most likely a direct consequence of HIV-1 infection of the CNS. The peripheral nervous system (PNS) is also affected in HIV-1-infected individuals and there are several features of immune- and cytokine-related pathogenesis in both the CNS and PNS that are reviewed. Several lines of evidence demonstrate aspects of immune activation in the CNS and peripheral nervous system (PNS) of HIV-1-infected individuals. The relative paucity of HIV-1 expression in contrast to widespread functional and pathologic changes in the CNS and PNS of AIDS patients, and the lack of evidence of productive infection of HIV-1 in neuronal cells in vivo lead to the possibility of indirect or immunopathogenic mechanisms for HIV-1-related neurologic diseases. Proposed mechanisms of neuronal and glial cell damage are injury of oligodendrocytes by tumor necrosis factor-alpha (TNF-alpha) released from activated macrophage/microglia, calcium-dependent excitoneurotoxicity induced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons triggered by interaction between cell surface receptors and HIV-1 gp120 protein. Common to those mechanisms is the dependence on cellular activation with expression of proinflammatory cytokines (TNF-alpha, interleukin-1). Amplification of activation signals through the cytokine network by macrophage/astrocyte/endothelial cell interactions, and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products. Expression of immunosuppressive cytokines such as interleukin-4, interleukin-6, and transforming growth factor-beta is also increased in the CNS and PNS of HIV-1-infected patients. This may serve as neuroprotective and regenerative mechanism against insults to nervous system tissue.

Reverse transcriptase-polymerase chain reaction showed that interleukin 3, IL-4, IL-5, IL-6, interferon-gamma and stem cell factor mRNA expression were higher in 15-deoxyspergualin-treated spleen cells than in control spleen cells. Increased IL-2 and IFN-gamma mRNA expression were observed in 15-deoxyspergualin-treated bone marrow cells. On the other hand, increased platelet counts in BALB/c-->C3H/He bone marrow chimeras were observed from days 20 to 33 in our previous work, when they were treated with 15-deoxyspergualin from days 14 to 25. In contrast, marked leukocytopenia and anemia were simultaneously observed, although a marked leukocytosis and a rapid recovery of anemia were observed on day 33 and thereafter. To analyze effects of 15-deoxyspergualin on hematopoiesis and the immune system, we examined mRNA expression in bone marrow and spleen cells from BALB/c-->C3H/He bone marrow chimeras treated with 15-deoxyspergualin from days 14 to 25. Reverse transcriptase-polymerase chain reaction showed that IL-3, IL-4, IL-6, stem cell factor, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor mRNA expression were higher in 15-deoxyspergualin-treated chimeras than in control chimeras, indicating that these cytokines are responsible for an enhancement of hematopoiesis. It was conceivable that IL-6 supported thrombopoiesis in concert with other cytokines. On the contrary, increased IFN-gamma, IL-2, IL-3, IL-4, and IL-10 mRNA expression may play an immunosuppressive role in vivo.

Langerhans cell histiocytosis (LCH) is characterised by an accumulation of cells ('LCH cells') with the same phenotypic features as normal Langerhans cells found in skin and other organs. The pathogenesis of LCH is unknown but there is increasing evidence to implicate the involvement of lymphokines and proinflammatory cytokines in the tissue damage seen in this disorder. Apart from histiocytes, the lesions contain giant cells, macrophages, neutrophils, eosinophils, lymphocytes, plasma cells and occasional mast cells that are the hallmark of an inflammatory process. The role of cytokines in the recruitment of haemopoietic cells within inflammatory lesions has only recently been recognised. In this article, we review the possible role of cytokines in the pathogenesis of LCH, and provide an overview of the methods currently used to detect and quantitate them. An appreciation of the type, distribution and amount of different cytokines released within lesions can provide clues to the possible aetiology of LCH. Using immunoassays, in situ hybridisation and RT-PCR, increased amounts of IL-1, IL-3, IL-4, IL-8, GM-CSF, TNF alpha, TGF beta and LIF have been demonstrated in LCH lesions. Lymphocytes constitutively produce GM-CSF and IL-3 and, to a lesser degree, IL-1, IL-4 and LIF whilst histiocytes produce TNF alpha, IL-1 beta and GM-CSF.

Cytokines are extracellular signalling glycoproteins that play an important pathological role in rheumatoid arthritis (RA) where they mediate acute inflammation, chronic inflammation and connective tissue destruction. In RA the macrophage-derived cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor (TNF), colony stimulating factors (CSFs) and growth factors play a key role in amplifying and perpetuating inflammation. IL-1 and TNF activate cartilage and bone degrading enzymes, while IL-8 recruits inflammatory cells into the joint. IL-1 and TNF play an important role in the acute phase response in that they potently induce IL-6, itself the major mediator and regulator of hepatic synthesis of acute phase proteins (APPs). The acute phase response is signalled by the rapid elevation of APPs such as C-reactive protein (CRP) and serum amyloid A (SAA) in the blood, and these can be used as good surrogate markers of disease activity. In health, the activity of cytokines such as IL-1 or TNF is checked by inhibitory molecules such as receptor antagonist molecules or soluble receptor molecules. In disease, cytokine activity appears to be relatively unopposed, leading to the recent development of cytokine inhibitory molecules as potential anti-RA therapies. However, while cytokines are mediators of disease, they probably do not provide the initial stimulus for RA to develop, although polymorphisms in TNF, IL-1 and IL-1 receptor antagonist genes which have been recently found may represent important genetic modifying factors of disease severity in RA.

Cytokines play important roles in the pathogenesis of lymphomas via an autocrine or a paracrine mechanism, or both. The characteristic clinical and histopathological features of malignant lymphomas may be due in part to elevated serum or tissue levels of cytokines. Determination of the effects of cytokines on the growth or differentiation of lymphoma cells is often complicated by the fact that more than one cytokine is responsible, and by the failure of anti-cytokine antibodies or antisense oligonucleotides to block the proliferation in vitro of lymphoma cells. However, it appears that IL-6 and/or IL-9 may play a prominent role in the tumor cell proliferation of Hodgkin's disease (HD), anaplastic large-cell lymphoma, or immunoblastic lymphoma. IL-6 may also be responsible for the plasmacytoid differentiation of lymphoma cells in polymorphic immunocytoma. The histopathological changes as a result of paracrine effects are most noticeable in HD. The malignant (H-RS) cells of HD have been shown to express IL-1, IL-5, IL-6, IL-9, TNF-alpha, M-CSF, TGF-beta, and CD80, and, less frequently, IL-4 and G-CSF. These cytokines may be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression found in patients with HD. In contrast to H-RS cells, most non-HD lymphoma cells do not produce cytokines in excess amounts and reveal only a minimal cellular reaction. Exceptions include T-cell-rich B-cell lymphoma, angiocentric T-cell lymphoma, and angio-immunoblastic lymphadenopathy (AILD-like T-cell lymphoma. IL-4 is responsible for the T-cell reaction in T-cell-rich B-cell lymphoma, whereas IL-6 accounts for the plasma cell reaction in AILD-type T-cell lymphoma. The authors extensively review the role of cytokines in lymphomas because this may lead to major advances in the understanding of the molecular processes involved in the histopathogenesis of lymphomas.

Various cytokines can be used in the treatment of solid tumours. They are factors of proliferation and/or differentiation of haematopoiesis or immunopoiesis, and they stimulate the effector cells of anti-tumoral response. The various steps in the preclinical and clinical development of a cytokine in the field of oncology are detailed, taking IL-2 as an example. The results of the clinical trials reported (essentially with INF and IL-2) are presented and discussed.

According to the type of secondary structure, cytokines are classified into three categories: alpha-spiral (IFNs-alpha, beta, omega, gamma; ILS-2, 3,4,5,6,7,9; CSFs-G, M, GM, MGF, PDGF), beta-structural (ILs-1 alpha, beta, TNFs-alpha, beta, FGF) and (alpha + beta)-structural proteins (IL-8, IFN-gamma IP-10, PF-4, bTG, GRO, 9E3). According to the type of tertiary structure, alpha-spiral proteins are grouped into IFN- and IL-2-like families and beta-structural ones into IL-1-, and TNF-like families. Two subfamilies can be identified in the IFN-like family. Theoretical and experimental evidence suggests that the genes IFNs are products of divergent or convergent evolution towards the gene of the ancient intracellular protein alpha-prothymosine, which is evolutionally in turn associated with the L7/I1 protein of two ribosomes. It is suggested that the proteins of the immunoglobulin superfamily, including cytokine receptors descended from the ancient proteins of the unicellular organisms molecular shaperons.

This review assesses recent data concerning the role of cytokines produced by a variety of cells in bone on osteoblast function. The following themes are presumed: (1) osteoblasts are mesenchymal cells which act as either the major cellular agents of bone formation or as modulators of bone resorption by osteoclasts. The regulation of osteoblast proliferation and differentiation may involve a negative feedback process resulting in phenotype suppression; (2) cytokines including platelet-derived growth factors (PDGF), parathyroid hormone-related proteins (PTHrP), bone morphogenic proteins (BMP), transforming growth factor beta (TGF beta), fibroblast growth factors (FGF), insulin-like growth factors (IGF), epidermal growth factors (EGF), interleukin-1 and 6, tumour necrosis factors (TNF), interferon and haematopoietic growth factors have effects on osteoblast differentiation and proliferation but their effectiveness may not be identical in vitro and in vivo; (3) finally, therapeutic strategies for cytokine use in clinical practice are considered.

Classic allergic responses occur as a result of mast cell-bound IgE being cross linked by allergen, causing degranulation and activation with release of multiple biologically active mediators. Such mediators may have a direct effects on target tissues and/or promote the inflammatory milieu typical of late-phase responses. The production of IgE is a normal T-cell dependent antibody response. It is the specificity for allergens that is aberrant, resulting in a hypersensitivity state. Recent work has demonstrated that small molecular weight substances called cytokines are responsible for many immunological activities such as IgE production, mast cell and eosinophil maturation, and proinflammatory mediators that directly contribute to the pathology of late-phase allergic responses. Differences are being sought in the relative production of various cytokines that can be correlated with disease activity. This should find clinical use in diagnosis, prognosis, and/or monitoring of specific immunotherapy. Additionally, therapeutic agents are being sought that have various agonist/antagonist properties to correct aberrant cytokine production. Such agents likely will have a central role in future therapy for allergic diseases.

By differential hybridization of cDNA libraries from Fv-1 restrictive and non-restrictive somatic mutant mouse cells, we isolated a cDNA clone specifically present in the Fv-1 restrictive cells. Its sequence was found identical to that of heparin-binding growth-associated molecule or pleiotrophin (HB-GAM/PTN). We report here its genomic organization which has not been yet reported. Although the exon organization was similar to that of midkine, another member of the same family of heparin-binding factors, the sizes of introns were much larger and occupied more than a three-fold larger chromosomal region than midkine. As its introduction into Fv-1 non-restrictive cells failed to confer the Fv-1 restrictive character, HB-GAM/PTN is probably unrelated to Fv-1 restriction.

Cytokines are glycoproteins produced by many different cells. Via binding to specific receptors on target cells they regulate the activation, differentiation, and proliferation of immune and nonimmune cells. After injury keratinocytes synthesize and release cytokines such as interleukins, colony stimulating factors, and growth factors. In addition, a network of interacting cytokines appears to be crucial to maintain proper balance. Dysregulation may contribute to certain diseases, particularly those of infectious and autoimmune origin. Therefore many of these mediators appear to be promising candidates to treat infectious and malignant diseases. This article briefly discusses the most important cytokines. Newly developed regimens with cytokines to treat cutaneous disorders will be reviewed.

Biotechnology has been fundamental to exploration and manipulation of life structures and processes at the molecular level. Regulation of expression of specific genes has impacted on understanding of cancer development and immunopathologic diseases. An even greater impact has been the production of new therapeutic molecules. Cytokines have been produced by recombinant DNA technology and are established as effective therapeutic modalities for cancer and infectious diseases. High quality pharmaceutical molecules have been produced which can substantially regulate cell function. Interferons typify this progress and are now licensed for both viral and neoplastic disease in more than 43 countries around the world. It seems certain that by the year 2000, the impact of biotechnology on human medicine will even be wider than that of today. Findings of biotechnology will have implications not only for advancement of human health but also will create debate regarding appropriate use.

The cytokines are multifunctional polypeptide hormones, produced by a variety of cells, that participate in the regulation of many biological processes. Essentially acting as intercellular messengers, they play a central role in the maintenance of homeostasis in normal tissues. Cytokines are key mediators of both local and systemic immune-inflammatory responses; therefore, disturbances in their secretion, response and/or regulation have been implicated in the pathophysiology of several conditions in which an exaggerated auto-destructive component appears to play a role. Conversely, deficits in cytokine production probably impair the host's ability to mount an effective immune response and may underlie the increased susceptibility to microbial infection observed, for example, in the neonate or in the malnourished patient. A review of the principal aspects of the biology of cytokines is presented together with the evidence supporting their involvement in several pathological states and the potential therapeutic applications of these mediators as novel immunomodulating agents.

A new era of immunotherapy is arriving in medical therapeutics. Both immunosupresion and immunomodulation have advantages which the clinician must learn. In this review, the author describe several immunomodulators which include cytokines, interleukins, interferons, tumor necrosis factor, granulocyte colony-stimulating factor, erythropoietin, and immunoglobulins. Some of these therapeutics approaches are already with us, and some are at present in the experimental stage.