Macrophage-Derived Growth Factors D. A.

RAPPOLEE* and

Z.

WERB

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8

Growth Factors Produced by Macrophages . . . . . . . . . . . . . . . . . . . . . . . .. Growth Factors Functionally Related to IL-l . . . . . . . . . . . . . . . . . . . . . . . .. Immediate-Response-Gene Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . Transforming Growth Factor-p . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Platelet-Derived Growth Factor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Transforming Growth Factor-IX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Fibroblast Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Colony-Stimulating Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Insulin-Like Growth Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

90 90 95 99 101 103 105 108 110

3

Negative Modulation of Macrophage-Derived Growth Factors . . . . . . . . . . . . . .

112

4

Inflammation

113

5

Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

116

6

Nerve Regeneration

119

7

The Immune Response

.....................................

120

8

Hematopoiesis

..........................................

121

9

Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

122

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

126

........................................... .......................................

1 Introduction In the early decades of the twentieth century biologists sought to grow cells in culture. Clotted blood was found to contain molecules that accomplished this purpose (CARREL 1912), but only later did biochemists seek to purify these molecules. By the middle of the century, biochemists and biologists sought to explain neonatal eye opening in mice in molecular terms (COHEN 1987; LEVIMONTALCINI 1987). Each of these goals ultimately led to the isolation of single species of molecules called growth factors by using in vitro or in vivo bioassays for growth and a biochemical algorithm for isolation. Epidermal growth factor * Current address: Departments of Obstetrics and Gynecology, and Cell, Molecular and Structural

Biology, Northwestern University, Chicago, IL 60611, USA Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, CA 94143-0750, USA Current TopICS

In

Microbiology and Immunology, Vol 181 Berlln'Heldelberg 1992

© Springer·Verlag

88

D. A. Rappolee and Z. Werb

(EGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), transforming growth factor-f3 (TGF-f3), interleukin-1 (IL -1), and macrophage colony-stimulating factor (M-CSF, or CSF-1) were isolated and directly sequenced or molecularly cloned (based on partial sequences) by these means in the 1970s and early 1980s. The production of transformed foci of cells by introduction of fragments of cloned transcripts or genes from tumors also produced a subclass of oncogenes that turned out to be growth factors [c-sis, or PDGF-B chain, and Kaposi's sarcoma-fibroblast growth factor (kFGF, or FGF-4)]. Most recently, the formation of tumors in vivo after random integration of a highly active viral promoter upstream of cellular genes has produced the int-1 and int-2 (also known as FGF-3) growth factors. Finally, after the founding member of a growth factor family is identified with a bioassay, low-stringency cDNA library screens and polymerase chain reaction can be used to complete the family (JAKOWLEW et al. 1988; HEBERT et al. 1990). All growth factors are operationally isolated and defined by their ability to cause growth, but may also act as non mitogenic inflammatory factors. Growth factors have a number of hallmarks. First, they are generally secreted and therefore act on nearby cells in a paracrine or autocrine fashion (Ross and VOGEL 1978). Some growth factors may exit cells slowly (e.g. IL-1, M-CSF) or on cell death (basic and acidic forms of FGF), but all enter the extracellular milieu. Other growth factors have a membrane-bound form (e.g., IL-1, M-CSF, TGF-()(, and EGF), but these growth factors also act locally between cells. The second hallmark of growth factors is that they tend to act in localized areas either within a cell (Ross and VOGEL 1978; Ross et al. 1986; DEUEL 1987) or within a few cell distances [as seen with NGF in pancreatic innervation (EDWARDS et al. 1989)]. Third, growth factors are generally not stored inside the cell (exceptions are PDGF and TGF-f3 in the platelet) but are highly inducible at the level of transcription (IL -1), translation [TGF-f3, tumor necrosis factor (TNF)-()(, IL-1] and post-translational activation (TGF-f3). Fourth, since these molecules are extremely powerful, they are tightly regulated at the various levels of production. They are unstable at the transcriptional level because of an AUUUA motif in the 3' untranslated area of many growth factor transcripts [c-sis/PDGF, IL-1, IL-2, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (SHAW and KAMEN 1986)], and at post-translational levels. PDGF and TGF-f3 are both inactivated by a macrophage product, ()(2-macroglobulin (DANIELPOUR and SPORN 1990; ROBERTS and SPORN 1990). In addition, the mediators of the growth factors (e.g., prostaglandins induced by PDGF or IL-1) have been demonstrated to negatively regulate the transcription of the inducing growth factor (KUNKEL et al. 1986; DANIEL et al. 1987). Fifth, growth factors are pleiotropic, acting as secretagogues, chemoattractants, and differentiation factors. Finally, growth factors act on the target cell through a transmembrane receptor. Some growth factors allosterically activate protein kinase activity on the cytosolic end of the receptor and trigger an amplified cascade of events within the target cell that lead to the pleiotropic events described. In some cases the growth factor receptor does not have intrinsic kinase activity but

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8) Debridement and phagocytosis

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11) Detoxification and storage of cellular (e.g., RBe) and molecular wastes

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Macrophage-derived growth factors.

Macrophage-Derived Growth Factors D. A. RAPPOLEE* and Z. WERB Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...
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