Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1443-1447
INTRODUCTION: FOCUS ON HEMATOLOGY
Resolving Conflicting Signals: Cross Inhibition of Cytokine Signaling
Pathways
By
C.G. Begley and
N.A. Nicola
From The Walter and Eliza Hall Institute for Medical Research, The
Cooperative Research Centre for Cellular Growth Factors and the Rotary
Bone Marrow Research Laboratories, Royal Melbourne Hospital, Victoria,
Australia.
 |
ARTICLE |
THE GENERATION of hematopoietic cells
requires the coordinated response to a plethora of stimulatory and
inhibitory signals that cells receive from their extracellular
environment. The "positive" regulators are relatively well
defined: the molecules that stimulate the proliferation,
differentiation, and survival of hematopoietic cells have been
extensively studied. These include the colony-stimulating factors
(CSFs) and the majority of the interleukins (ILs). Several of these
molecules are available for clinical use, and much is known about their
structure, the consequences of their over-production, and the
biological effects that result from their complete absence. The
multi-protein receptor complexes that are used by these molecules at
the cell surface have been characterized to reveal a complicated
interplay of shared receptor components and unique receptor elements.
More recently the intracellular pathways that are triggered by growth
factor/receptor interactions have begun to be dissected, revealing an
interdigitating network of signaling molecules that is striking both in
terms of its complexity, and in terms of the recurring themes that are
revealed in otherwise apparently divergent experimental
systems.1 By comparison, the "negative" regulators of
hematopoiesis have been relatively neglected. However, it has been
clear for a number of years that molecules like transforming growth
factor-
(TGF-) are potent negative regulators of hematopoiesis
and function as important molecules in determining hematopoietic responses.
The identification of the JAK/STAT signaling pathway provided an
understanding of one mechanism by which stimulatory signals received at
the cell surface are rapidly transmitted to the nucleus. The JAKs (or
Janus kinases) are receptor-associated molecules that are
phosphorylated on tyrosine in response to cytokine-receptor interactions. As a consequence, the STAT (for signal transducers and
activators of transcription) molecules are recruited to the receptor
and phosphorylated.2,3 This leads to their dimerization and
translocation to the nucleus where they bind and activate transcription
of target genes. The recruitment of particular JAK/STAT family members
overlaps but differs for different cytokines. Thus, for example, IL-6
type cytokines use JAK1, JAK2, and the related molecule TYK2, and STAT1
and STAT3,4,5 although the critical molecules appear to be
JAK1 and STAT3.6,7 In comparison, the IL-12 signaling
pathway results in phosphorylation of JAK2 and TYK28,9 and
requires STAT4 for IL-12-generated responses.10,11
The mechanism by which "negative" regulators exert their
inhibitory action is less clear. One possible mechanism involves the
recruitment of protein tyrosine phosphatases that can then serve to
inactivate JAK proteins. One such is SHP-1, the defective function of
which results in the hyperproliferation and accumulation of several
hematopoietic cell lineages and in the development of autoimmune
disease as evidenced by the motheaten mouse.12 Specific targeting of this molecule to the erythropoietin receptor can
inhibit ligand-stimulated tyrosine phosphorylation and result in
dephosphorylation of JAK2.13 The negative regulator TGF- has been reported to activate protein tyrosine
phosphatases14 and this may be one mechanism by which it
exerts its inhibitory effect on the JAK/STAT pathway.15
Another family of signaling molecules that are potentially important
mediators of inhibitory signals have recently been described. There
appear to be at least 8 of these "SOCS" proteins (for suppressors of cytokine signaling) including CIS, an early response gene, that
encode SH2-domain containing proteins16-19 and 12 others
that also share a C-terminal domain called the SOCS box.17
These proteins were identified simultaneously using three different approaches. One involved a functional screen for cDNAs encoding proteins that blocked IL-6 function.20 A second approach
involved a yeast two-hybrid strategy for proteins interacting with the kinase domain of JAK2.21 The third searched for proteins
with antigen similarity to the SH2 domain of the STAT
molecules.22 Cytokines induce the expression of the SOCS
genes, and the SOCS proteins then serve to downregulate the JAK/STAT
pathways and therefore curtail the biological response. Thus, for
example, SOCS1 (also known as JAB and SSI-1) is induced within 20 minutes after stimulation by IL-6 and suppresses the cellular response to IL-6 via its interaction with activated JAK proteins through its SH2
domain.23 Levels of SOCS1 expression return to baseline within about 4 hours. The transcriptional activation of SOCS genes is
mediated, at least in part by the STAT proteins; CIS expression is
modulated by STAT5 and STAT3 is important for SOCS1
expression.24 SOCS1 also attenuates the biological response
to a number of other cytokines including leukemia inhibitory factor,
oncostatin-M, interferon-
(IFN-), thrombopoietin, and growth
hormone.20,25 Moreover, as well as acting to reduce
phosphorylation of JAK kinases and STAT proteins, SOCS proteins may
function as more general inhibitory regulators.26,27
Therefore, these proteins are induced by cytokines, and act to suppress
cytokine signaling, acting in a classical negative feedback loop.
One situation in which a complex array of competing "positive"
and "negative" regulators is clearly evident, is in the
generation of cells important in antigen-specific or cell-mediated
immune responses. Studies of T-lymphocyte clones have identified two major subpopulations of CD4+ cells, T-helper lymphocyte
(TH) 1 induced by IL-12 and IFN- and TH2 cells induced
by IL-4.28-30 The development of the TH1 versus TH2
phenotype is dependent on cell-intrinsic as well as extrinsic
stimuli.31 These cells differ in the cytokines that they
produce after activation. Thus, a cellular immune response dominated by
a TH1 response is characterized by cells that produce IFN-, IL-2,
and TNF-. Conversely, a TH2 response is typified by the production
of IL-4, IL-5, IL-6, IL-13, and IL-10 (Fig 1). Both TH1 and TH2 cells
produce granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor-
(TNF-), and IL-3; however, the relative levels may
vary. These patterns of
cytokine expression can be used to categorize most murine
CD4+ T-lymphocyte clones, and as such, allow classification
in terms of the principal immune response induced in experimental
systems.32 This may also be relevant to some human disease
states.33 As expected from the differing cytokine
expression patterns, these subsets of cells also differ in their
functional properties, with TH1 cells being predominant in assisting
microbiocidal macrophage responses (via IFN- and TNF-) while TH2
cytokines augment B-cell responses. This divergence in function is
particularly evident during infection with the protozoa, Leishmania,
where macrophage activation is required for protection from this
intracellular parasite.34 In this system TH1-responses are
protective while TH2 responses fail to offer protection and lead to a
nonhealing of disease. In BALB/c mice, a bias toward a TH2 response,
with production of IL-4 and the requirement for STAT6-mediated
signaling,35 results in the genetic susceptibility to
Leishmania infection.
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| Fig 1.
(A) Cytokines controlling the development of
cell-mediated (TH1) and humoral (TH2) responses. Certain infections
such as viruses induce the production of IL-12 and IFN- by antigen
presenting cells (APC). These factors promote the differentiation of
TH0 cells to the TH1 phenotype. Other infections such as helminths
induce the production of IL-4 (by eosinophils) which induces
differentiation to the TH2 phenotype. TH1 cytokines such as IFN-
inhibit the production of IL-4 and IL-10 while TH2 cytokines such as
IL-10 inhibit the production and action of IL-12. (Part B) Factors such
as IL-12 and IFN- activate a cascade of intracellular signaling
molecules including molecules in the JAK/STAT pathway. In contrast,
inhibitory molecules may produce their inhibitory effects in part via
the activation of molecules such as phosphatases in the case of
TGF-, and SOCS genes in the case of IL-10. These pathways would
serve to attenuate a biological response.
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In this context, IL-12 and IFN- are important, proinflammatory
cytokines that act as a powerful inducers of a TH1
response.36,37 IL-12 is also active on natural killer (NK)
cells. IL-12 is produced by antigen-presenting cells (APC) as a result
of an interaction, via CD40 and its ligand, between the APC and
activated T lymphocytes.38,39 In this incestuous
relationship, the production of IL-12 by APC is further stimulated by
the TH1 cells and their product IFN- and vice
versa.40,41 Conversely, a defect in the production of IL-12
and IFN- may be important in impaired TH1-mediated immune responses,42,43 with evidence that IL-12 and IFN-
production, and the IL-12 responsiveness of TH1 cells, can be
antagonized by TH2 cells and the cytokines that they produce (IL-10,
IL-4, IL-13).44,45
The target cell for the action of IL-12, the activated T cell, is also
subject to additional opposing, inhibitory cytokine influences. TGF-
is an immunosuppressive molecule that, in addition to its inhibitory
action on lymphoid cells, inhibits proliferation, differentiation, and
functional activity of myeloid cells and NK cells. TGF- can
interfere with IL-2-mediated tyrosine phosphorylation and activation
of JAK1 and STAT515 and with multiple components of the
IL-5 signaling pathway including an inhibitory effect on JAK2 and
STAT1.46 In the report in this issue by Pardoux et al,47 the mechanism by which the inhibitory effect of
TGF- is able to oppose the stimulatory action of IL-12 on activated T cells is addressed: how does an activated T-cell resolve these conflicting signals?
As outlined above, IL-10 (along with IL-4 and IL-13) is an
anti-inflammatory cytokine produced by TH2 cells.48,49 It
serves to maintain a TH2-type immune response in part by preventing the development of TH1 cells, thereby preventing production of the macrophage activating molecules such as IFN-. IL-10 is also produced by monocytes in response to lipopolysaccharides. In addition to its
action on lymphoid cells, IL-10 acts as a direct inhibitor of
macrophages, inhibiting gene transcription and inhibiting production of
inflammatory cytokines.50-52 Thus, as well as being a
product of TH2 cells, IL-10 has an auto-regulatory role in
monocytes53 and its production by monocytes is inhibited by
the proinflammatory molecule IFN-.54 What are the
mechanisms by which the opposing influences of IL-10 and IFN- are
reconciled within the monocyte? In the accompanying report by Ito et
al55 these authors examine the mechanisms by which the
action of IL-10 and IFNs are balanced.
Pardoux et al have taken advantage of their recent demonstration that
TGF- inhibited the development of cytotoxic and proliferative allogeneic (TH1) responses by a mechanism that involved decreased production of IL-12.56 They further observed that
TGF--mediated inhibition of alloreactive T cells was not overcome
by the addition of exogenous IL-12. This was confirmed in their report
in this issue by the demonstration that addition of IL-12 was not able to completely overcome the inhibitory effect of TGF- on IFN- production by these cells. They reasoned that this failure implied that
TGF- also interfered either with IL-12 receptor expression on the
activated T cell, or with the signal transduction pathway initiated by
IL-12 receptor. They showed that the former was not the case; there was
no consistent difference in IL-12 receptor expression in response to
TGF-. The addition of TGF- did not alter the levels of JAK2 and
Tyk2, two intracellular signaling molecules normally phosphorylated in
response to IL-12; however, there was a significant decrease in the
tyrosine phosphorylation of both molecules within 20 minutes of
incubation with TGF-. A consequence of activation of JAKs is the
phosphorylation of STAT molecules, with STAT4 being activated in
response to IL-12 signaling. Again there was no decrease in the level
of STAT4 protein but tyrosine phosphorylation and DNA binding activity
of STAT4 were decreased in response to TGF- within 20 minutes. Thus,
these results suggest that TGF- directly interferes with
intracellular signaling by IL-12 and the authors suggest that this may
be mediated by TGF--induced tyrosine phosphatases (Fig 1).
The results presented by Ito et al55 are remarkably
similar, but they provided additional evidence that may further explain the mechanism by which interference at the level of intracellular signaling occurs. The authors showed that IL-10 inhibited the transcription of some genes normally induced in human monocytes in
response to stimulation with IFN- and IFN-. Consistent with the
studies by Pardoux et al, there was no change in number or affinity of
IFN- receptors in response to treatment with IL-10. Similarly, IL-10
did not alter the levels of STAT1, the principal target for IFN-
signaling in these cells, but decreased the phosphorylation of STAT1
and decreased DNA binding activity. These inhibitory effects of IL-10
were more evident when lower concentrations of IFN were examined. There
was no evidence that this effect of IL-10 was due to induction of
phosphatase activity. However, this study presents a result that
potentially could explain the observations reported in both papers.
These authors showed that treatment of monocytes with IL-10 induced the
expression of the SOCS3 gene within 30 minutes and maintained its
expression for at least 120 minutes. These kinetics are consistent with
the observed action of IL-10 to inhibit IFN-induced STAT1 activation
and IFN-stimulated gene expression. Although studies have shown that in
myeloid and fibroblast cell lines SOCS1 but not SOCS3 was an inhibitor
of IFN- signaling,57,58 more recent results have also
implicated SOCS3 as an inhibitor of IFN signaling.59 It
will be important to determine whether other SOCS proteins are induced
by IL-10.
Together, these results suggest that one mechanism by which inhibitory
cytokines exert their effect is via the direct activation of inhibitory
signaling pathways like phosphatases and SOCS proteins. The SOCS
pathway is a potential candidate for mediating this type of response
because SOCS proteins are normally activated in response to positive
cytokine signals, thus ensuring that a biological response is
transient. Direct access to these same signaling molecules by
inhibitory cytokines provides an attractive and efficient mechanism whereby competing signals are resolved to redirect a cellular response.
It seems possible that this might prove a common mechanism for cells
faced with alternate choices and competing extracellular demands.
| |
FOOTNOTES |
Address reprint requests to C.G. Begley, MD, The Walter
and Eliza Hall Institute of Medical Research, PO Royal Melbourne
Hospital, Parkville, 3050 Victoria, Australia.
| |
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A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons.
Blood
92:1668, 1998[Abstract/Free Full Text]
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Suzuki R, Sakamoto H, Yasukawa H, Masuhara M, Wakioka T, Sasaki A, Yuge K, Komiya S, Inoue A, Yoshimura A:
CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells.
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Song MM, Shuai K:
The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities.
J Biol Chem
273:35056, 1998[Abstract/Free Full Text]
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