Somatostatin

David E. Elliott*
Division of Gastroenterology, Department of Medicine, University of Iowa, 4611 JCP, Iowa City,
IA 52242, USA
* corresponding author tel: 319-353-8574, fax: 319-353-6399, e-mail: david-elliott@uiowa.edu
DOI: 10.1006/rwcy.2001.13008.

SUMMARY Figure 1 Preprosomatostatin.

Somatostatin is a small cyclic peptide with anti-

inflammatory and immunoregulatory properties. It is
made by nerve, endocrine, and inflammatory cells.
Somatostatin and somatostatin agonists inhibit
inflammation in several animal model systems and
in human diseases. Somatostatin acts on T cells to
inhibit antigen-stimulated IFN release. It is made by
activated macrophages within inflammatory lesions.
Cytokines such as IFN or IL-10 and inflammatory
mediators such as LPS or prostaglandin E2 induce
normal splenic macrophages to make somatostatin.
Somatostatin is a highly conserved peptide that
functions as a neurotransmitter, a hormone, and an
inducible immunoregulatory cytokine.

different forms of mature somatostatin exist. Pro-

BACKGROUND
Discovery
Somatostatin was discovered in 1973 (Brazeau et al.,
1973) as a somatotropin (growth hormone) release
inhibiting factor (SRIF). Somatostatin is abbreviated
SST, SOM, or SRIF. Somatostatin-producing cells
have been identified throughout the body, where it
functions as a neurotransmitter, a hormone, or a
cytokine-like paracrine/autocrine regulator of cell
function (Patel, 1999). Somatostatin is made by all
vertebrate, and some invertebrate and plant species.
Somatostatin is initially synthesized as an inactive
preprosomatostatin consisting of 116 amino acids
(Figure 1). The active peptide is located at the C-
terminus of the prepromolecule. The 24 amino acid
leader sequence is cleaved in the endoplasmic reticulum
to yield a 92 amino acid prosomatostatin protein. Two
somatostatin can be cleaved into either a 28 amino acid
form (SOM 28) or a 14 amino acid form (SOM 14). It is
the 14 amino acid peptide that is immunoregulatory.
Alternative names
SOM, SOM-14, SST, SST-14, SRIF.
Structure
Somatostatin is a cyclic peptide due to a cystine thiol
bond (Figure 2). The thiol bond helps to hold phenyl-
alanine, tryptophan, lysine, and threonine in conforma-
tion. This amino acid loop is present in octreotide
(SMS 201±995, Sandostatin), which is a stable agonist
of somatostatin. The formula for octreotide is: H-(D)-
Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol, (the cyste-
ines are crosslinked). Somatostatin agonists have
clinical utility, prompting analysis of the pharmacology

Cytokine Reference Copyright # 2001 Academic Press

2 David E. Elliott

Figure 2 Somatostatin 14. Human preprosomatostatin mRNA: J00306 (Shen

et al., 1982)
Mouse preprosomatostatin gene: X51468 (Fuhrmann
et al., 1990)
Rat: J00787
Pig: P01168
Sheep: AF031488
Cow: M31217
Cat: L42325
Chicken: X60191
Frog: U68136
Lungfish: AF126243
and structure of somatostatin and its agonists. There are Goldfish: U40754
five different receptors for somatostatin. The precise Catfish: M25903
stereospecific requirements of ligands for each receptor
is being elucidated. Sequence
For human gene and mRNA sequences see Figure 3
Main activities and from accession number J00306. Features of the
pathophysiological roles human somatostatin gene on chromosome 3q28 are:
50 flank (promoter region): 1±1125
Somatostatin is highly conserved in vertebrates and Transcriptional start site: 1126
regulates secretion of many hormones such as growth CDS: (1231±1368) joined to (2246±2458)
hormone, calcitonin, insulin, gastrin, and renin. Exon 1: 1231±1368
Clinically, somatostatin agonists are used to control Intron 1: 1369±2245
aberrant hormone production. Somatostatin also Exon 2: 2246±2605
regulates inflammation and T cell function. Somatostatin 28 sequence: 2372±2455
Importantly, somatostatin is made at sites of Somatostatin 14 sequence: 2414±2455
inflammation (Weinstock et al., 1990). Inflammatory For mouse preprosomatostatin gene and mRNA
mediators and cytokines can induce somatostatin sequences see Figure 4. Features of the mouse gene are:
production by murine macrophages. Somatostatin 50 flank (promoter region): 1±795
and agonists of somatostatin inhibit inflammatory Transcriptional start site: 796
reactions in mice (Blum et al., 1992; Bowman et al., CDS: (896±1033) joined to (1699±1911)
1996), rats (Karakalis et al., 1994, rabbits (Matucci- Exon 1: 896±1033
Cerinic et al., 1995), and humans (Coari et al., 1995; Intron 1: 1034±1698
Fioravanti et al., 1995; Matucci-Cerinic et al., 1988; Exon 2: 1699±2059
Krassas et al., 1997). Thus, somatostatin functions in
a feedback mechanism to regulate inflammatory
reactions. Chromosome location
T cells constitutively express receptors for soma-
tostatin (see SSTR2 chapter). Somatostatin inhibits Human gene is on chromosome 3q28.
murine T cell release of IFN (Blum et al., 1992;
Elliott et al., 1999). Somatostatin regulates IFN -
mediated TH1 effects such as B cell switching to PROTEIN
IgG2a in mice (Blum et al., 1993). Thus, somatostatin
regulates TH1/TH2 circuitry. Accession numbers
Human somatostatin: J00306
GENE AND GENE REGULATION Mouse preprosomatostatin: X51468
Rat: J00787
Accession numbers Pig: P01168
Sheep: AF031488
Human somatostatin gene: J00306 (Shen and Rutter, Cow: M31217
1984) Cat: L42325
 Somatostatin 3

Figure 3 Nucleotide sequences for the human
somatostatin gene on chromosome 3q28. Lower
case is not transcribed. Uppercase is transcribed.
Protein-coding sequence shown in bold.
Figure 4 Nucleotide sequences for the mouse pre-
prosomatostatin gene (from X51468) and mRNA.
Lower case is not transcribed. Uppercase is tran-
scribed. Protein-coding sequence shown in bold.
TATA box shown underlined.

Chicken: X60191
Frog: U68136 Figure 5 Amino acid sequence for proprosomatostatin
Lungfish: AF126243 protein deduced from mRNA sequence.
Goldfish: U40754
Catfish: M25903

Sequence
See Figure 5.
4 David E. Elliott

Important homologies includes 795 bp of the promoter region proximal to

Somatostatin is highly conserved, sharing a great deal
of homology between species. Two genes for
somatostatin exist in fish, probably due to gene
duplication. Table 1 includes the fish gene with most
homology to the mammalian gene.
CELLULAR SOURCES AND
TISSUE EXPRESSION
Cellular sources that produce
Somatostatin is made in many tissues. The brain,
hypothalamus, thymus, and intestine are particularly
rich sources. Splenocytes from normal mice normally
do not make somatostatin. However, macrophages
and IL-10 to induce
within the spleen are induced to make somatostatin
by some cytokines and inflammatory mediators
(Blum et al., 1998). Somatostatin is made in spleens
from animals with chronic inflammation (e.g.
schistosomiasis).
(Blum
Eliciting and inhibitory stimuli,
release by antigen-stimulated T cells.
including exogenous and
release. IL-4 alone
endogenous modulators
Transcription of the somatostatin gene is regulated.
The gene sequence shown in Figure 3 and Figure 4
the transcription start site. Immediately before the
noncanonical TATA box is the GAGA box
(AGAGAGAGA) that controls somatostatin expres-
sion in endocrine cells. Adjacent to the GAGA box is
a CREB (cyclic AMP responsive element binding)
site (TGACGTCA) that confers cAMP-initiated
transcription.
We showed (Blum et al., 1998; Elliott et al., 1998)
that macrophages from normal mice make and
release somatostatin after 4 hours exposure to IFN
(200 U/mL), IL-10 (30 ng/mL), LPS (30 g/mL),
PGE2 (110ÿ6 M), or a cAMP analog (110ÿ4 M).
Thus, macrophages make and release somatostatin in
response to several cytokines and inflammatory
mediators. Prostaglandin and cAMP analogs are
probably inducing transcription via CREB interac-
tions. LPS likely signals through NFB. The signaling
pathways utilized by IFN
macrophage somatostatin transcription is currently
being studied.
Importantly, the somatostatin mRNA level is also
negatively regulated. The neuropeptide/cytokine sub-
stance P decreases somatostatin transcripts in splenic
macrophages stimulated with IL-10 or IFN
et al., 1998). In contrast to somatostatin, substance P
promotes IFN
Substance P prevents production of somatostatin that
would serve to inhibit T cell IFN
does not induce somatostatin transcription but it
prevents substance P-mediated decrease in somatos-
tatin mRNA. Thus, TH1/TH2 cytokines regulate
macrophage somatostatin production.

Table 1 Percentage identity of somatostatin protein between species

Animal Accession number Preprosomatostatin Prosomatostatin Somatostatin 14

Mouse (Mus musculus) X51468 96 98 100

Rat (Rattus norvegicus) J00787 96 98 100
Pig (Sus scrofa) P01168 ± 100 100
Sheep (Ovis aries) AF031488 99 100 100
Cow (Bos taurus) M31217 98 99 100
Cat (Canis familiaris) L42325 98 100 100
Chicken (Gallus gallus) X60191 87 91 100
Frog (Rana ridibunda) U68136 76 84 100
Lungfish (P. annectens) AF126243 72 78 100
Goldfish (C. auratus) U40754 68 73 100
Catfish (I. punctatus) M25903 58 61 100

RECEPTOR UTILIZATION
There are five different somatostatin receptors named
SSTR1 to SSTR5. Human and murine inflammatory
cells express SSTR2.
IN VITRO ACTIVITIES
In vitro findings
Somatostatin and octreotide inhibit antigen-induced
IFN
release from granuloma and splenic T cells of mice
with schistosomiasis (Blum et al., 1992; Elliott et al.,
1999). This effect is most substantial when T cells are
stimulated with low doses of antigen. The physiologic
effects of IFN
inhibition by somatostatin and exocrine activity of many cell types. Somatostatin de-
octreotide is reflected in the reduction of splenic and
granuloma B cell IgG2a production in vitro and in vivo
(Blum et al., 1993; Elliott et al., 1999).
Treatment with exogenous somatostatin or octreo-
tide regulates granulomatous inflammation in murine
schistosomiasis. Importantly, somatostatin is also
made in the granulomas. Granuloma macrophages
synthesize and release somatostatin 14 (Weinstock
et al., 1990; Elliott et al., 1998). Normal splenic
macrophages do not make somatostatin constitu-
tively but will transcribe and synthesize the peptide
after 4 hours exposure to IFN
, IL-10, LPS, PGE2, or schistosomes develop granulomas around the parasite
cAMP analog. Thus, somatostatin functions as an
inducible cytokine to downregulate T cell function.
Somatostatin may regulate many different cell types
within the granuloma cell population. For example,
somatostatin may influence antigen-presenting cells to
inhibit T cell IFN
release. However, somatostatin does Somatostatin can regulate inflammation in several
act directly on T cells. Somatostatin inhibits IFN
other model systems. Somatostatin suppressed the
release by cloned D1.1 T cells stimulated with cross-
linked monoclonal anti-CD3 and anti-CD4 in the
absence of antigen-presenting cells (Elliott et al., 1999).
Bioassays used
Tissue and cellular somatostatin production is
measured by acid extraction, HPLC fractionation,
and radioimmunosorbant assay (RIA) on the HPLC
fractions to obtain a quantitative measurement
(Weinstock et al., 1990; Blum et al., 1998).
Somatostatin 5
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Normal physiological roles
In addition to controlling growth hormone release,
somatostatin regulates many diverse physiologic func-
tions. The list of regulatory functions includes
inhibition of: thyroid-stimulating hormone release,
TSH-mediated thyroxine release, parafollicular cell
calcitonin release, pancreatic islet hormone secretion
(e.g. insulin), renin release by the juxtaglomerular cells
of the kidney, stomach G-cell gastrin production (there-
by regulating gastric acid production), and bile produc-
tion. In general, somatostatin inhibits endocrine and
creases gall bladder contractility, gastric emptying, and
segmental intestinal motility but stimulates the intes-
tinal migrating motor complex. Somatostatin suppres-
ses proliferation of many cell types including cancers.
The ability of this small peptide to have diverse func-
tions is explained by the presence of five different somato-
statin receptors. T cells, B cells, and macrophages
express somatostatin receptor subtype 2 (SSTR2).
Somatostatin 14 is an immunoregulatory peptide.
Somatostatin regulates the granulomatous response
of schistosome-infected mice. Mice infected with
eggs that lodge in the liver and intestine (schistoso-
miasis) (Elliott, 1996). Mice treated in vivo with
octreotide (a stable SOM14 agonist) develop granu-
lomas 60% the size that form in sham-treated mice
(Blum et al., 1992).
carrageenan inflammatory reaction in rats (Karalis
et al., 1994). Treatment with somatostatin delayed
onset of diabetes in the NOD-scid/scid transfer model
of murine insulin-dependent diabetes mellitus (IDDM)
(Bowman et al., 1996). Intra-articular injection of
somatostatin reduced established fibrin-induced
arthritis in rabbits (Matucci-Cerinic et al., 1995).
Octreotide treatment decreased colonic mucosal
platelet-activating factor, and leukotriene B4 content
and inhibited mucosal damage in rats with acetic
acid-induced acute colitis (Eliakim et al., 1993).
Administration of octreotide decreased colonic
Somatostatin can be identified in cells by immu-
in the rat trinitrobenzene
nohistochemistry using monoclonal antibody
CURE.S607 (Blum et al., 1998; Wong et al., 1990).
Murine preprosomatostatin mRNA can be mea-
sured using a quantitative competitive RT-PCR assay
(Elliott et al., 1998).
TNF, IL-1, and IFN
sulfonic acid (TNBS) model of colitis (Lamrani et al.,
1999).
Somatostatin and its analogs reduce inflammation
in patients with rheumatoid arthritis, psoriatic
arthritis, and Graves' disease.
6 David E. Elliott
IN THERAPY
Preclinical ± How does it affect
disease models in animals?
Agonists
Somatostatin has been used in patients with inflamma-
tory diseases. Intra-articular injection of somatostatin
reduces synovitis in patients with rheumatoid arthritis
(Coari et al., 1995; Fioravanti et al., 1995). Somatostatin
infused over 48 hours reduced polyarticular joint pain
and skin lesions in 12 of 18 patients with psoriatic
arthritis (Matucci-Cerinic et al., 1988). Lanreotide, a
long-acting somatostatin analog, significantly
improved the inflammatory ocular manifestations of
Graves' disease (Krassas et al., 1997).
Stable analogs of somatostatin are used clinically to
manage several other diseases and conditions. These
include acromegaly (Newman, 1999), carcinoid syn-
drome (Oberg, 1998), chronic diarrhea (Farthing,
1996), and bleeding esophageal varices (Hadengue,
1999). Somatostatin suppresses growth of none-
ndocrine neoplasms in several model systems
(Hofland and Lamberts, 1997; Pollak and Schally,
1998). Unfortunately, clinical trials have not shown
efficacy for somatostatin analogs in treating breast
cancer (O'Byrne et al., 1999; Ingle et al., 1999).
Many endocrine and nonendocrine neoplasms
avidly bind radiolabeled somatostatin analogs. This
allows the scintigraphic localization of primary and
metastatic lesions to aid surgical resection
(Kwekkeboom and Krenning, 1997). Recently,
intensely labeled analogs have been used to concen-
trate radioisotopes at the site of malignancies.
Scintigraphy with radiolabeled somatostatin ago-
nists demarcates areas of granulomatous inflamma-
tion in patients with diseases such as Wegener's
granulomatosis, tuberculosis, sarcoidosis, and aspergil-
losis (Ozturk et al., 1994; van Hagen et al., 1994a,
1994b, 1994c; Postema et al., 1996). This demon-
strates that cells within an inflammatory reaction
express receptors for somatostatin (John et al., 1996).
Antagonists
Antagonists for somatostatin have been identified
(Bass et al., 1996; Hocart et al., 1998) but have not
been clinically applied.
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ACKNOWLEDGEMENTS
Grants from the National Institutes of Health
(DK02428).