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Renaming cytokines: MCP-1, Major Chemokine in Pancreatitis
  1. F Marra
  1. Correspondence to:
    Dr F Marra
    Dipartimento di Medicina Interna, University of Florence, Viale Morgagni, 85, I-50134 Florence, Italy;

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Evidence of a mechanistic role for monocyte chemoattractant protein 1 (MCP-1) in the pathogenesis of inflammation and fibrosis associated with experimental pancreatitis

Fibrosclerotic organ diseases, a major cause of morbidity and mortality in the Western world, involve tissues as diverse as the liver, kidney, heart, lung, skin, and intestine. The causes of these diseases are manifold, and specific noxae are implicated in different settings. Nevertheless, most (if not all) of these conditions share common pathogenetic grounds, such as being characterised by derangement of the tissue “wound healing” response. The ability of tissues to respond to injury has evolved to neutralise infectious agents and to limit parenchymal cell damage. The wound healing response comprises recruitment of inflammatory cells, deposition and remodelling of extracellular matrix, and regeneration (or an attempt thereof) of parenchymal cells. The ultimate outcome of this process is dependent on the duration of damage, and on the ability of parenchymal cells of specific tissues to reconstitute the original architecture. Thus chronic damage is often characterised by simultaneous and uncoordinated activation of all components of the wound healing response, resulting in chronic inflammation, destruction of the parenchyma, and progressive scarring. Chronic pancreatitis is a typical example of the transferability of these concepts to the clinical field. In response to several causes, most frequently alcohol abuse, metabolic abnormalities, or autoimmunity, damage to acinar cells leads to chronic inflammation, eventually resulting in substitution of pancreatic parenchyma with bundles of scar tissue and loss of function.1

The contribution of inflammation to the development of fibrosis varies in different conditions, and understanding the interaction between these processes is relevant to devise therapeutic strategies for chronic diseases such as pancreatitis. Identification of the chemokine system has elucidated the molecular mechanisms regulating leucocyte trafficking in a given tissue. Chemokines are a family of small cytokines that exert gradient dependent chemoattraction of cells bearing specific cognate receptors. The chemokine system is considerably complex, as indicated by the high number of ligands and receptors, and by the fact that the same chemokine may bind more than one receptor and the same receptor more than one chemokine.2 Additionally, the effects of chemokines are not limited to inflammation as the majority of cells express at least one chemokine receptor. A related aspect of chemokine biology is the distinction between “homeostatic” and “inflammatory” chemokines, where expression of the latter ones is low in normal tissue, to be upregulated in conditions of injury.2 Inflammatory chemokines are obviously, although not exclusively, associated with chemoattraction of leucocytes.

Monocyte chemoattractant protein 1 (MCP-1 or CCL2) is a prototypic inflammatory chemokine, which targets monocytes, T lymphocytes, and other cells expressing the C-C chemokine receptor (CCR2).3 Remarkably, MCP-1 not only provides chemotactic cues for the recruitment of monocytes from the bloodstream to the tissue but is also responsible for monocyte activation and induction of the respiratory burst.4 The conditions in which MCP-1 has been implicated in the development of acute or chronic inflammation are almost countless, and pancreatitis is no exception. In fact, upregulated MCP-1 expression has been found during acute and chronic pancreatitis both in animal models and in human tissues, suggesting the contribution of this chemokine in the pathogenesis of mononuclear infiltration.5–7 However, MCP-1 is only one of several chemokines upregulated in pancreatitis, and evidence for its pathogenic role was lacking.

A paper in this issue of Gut by Zhao and colleagues8 provides compelling evidence of a mechanistic role for MCP-1 in the pathogenesis of inflammation and fibrosis associated with experimental pancreatitis (see page 1759). Rats administered a single intravenous injection of the organotin compound dibutyltin dichloride develop pathological changes closely resembling those of human chronic pancreatitis. Acute oedema and neutrophilic infiltration are followed after a week by mononuclear inflammation and activation of matrix producing cells, most likely represented by pancreatic stellate cells (PSCs) undergoing activation.9 Eventually, deposition of fibrillar collagen leads to extensive fibrosis, replacing most of the pancreatic parenchyma. In this model, Zhao and colleagues8 have investigated the effects of MCP-1 neutralisation obtained by intramuscular injection of a plasmid encoding for a form of MCP-1 mutated at the N terminus ((1, 9–76) MCP-1) and capable of blocking its biological actions.10 This antichemokine gene therapy resulted in a dramatic amelioration of pancreas pathology, preservation of exocrine secretory function, and reduction of inflammation and fibrosis.

Demonstration that interfering with MCP-1 may be sufficient to block evolution to end stage experimental pancreatic damage has clear implication for our knowledge of the pathophysiology of chronic pancreatitis and pancreatic fibrosis. In addition, these data allow us to focus on the multiple levels of interaction between inflammatory cells and fibrogenesis within the inflamed pancreas. The first and most obvious level highlighted by the present study is the profibrogenic role exerted by infiltrating mononuclear phagocytes. Activated monocytes and macrophages express cytokines that target mesenchymal cells participating in tissue specific wound healing, including platelet derived growth factor and transforming growth factor β1. Within the pancreas, PSC have recently been identified as the main matrix producing cells during damage, and their biology closely resembles that of fibrogenic cells in other districts, including glomerular mesangial cell, vascular smooth muscle cells, and hepatic stellate cells.11 Thus platelet derived growth factor is a potent mitogen and chemoattractant for PSCs, and transforming growth factor β upregulates the expression of many extracellular matrix proteins, including fibrillar collagens.11 In addition, inflammation dependent generation of oxidative stress related products provides additional stimuli for the modulation of the fibrogenic process in different cell types, including PSCs. It is therefore not surprising that control of inflammation obtained by interfering with the actions of MCP-1 was associated with downregulation of profibrogenic cytokines and fibrosis in the Zhao study.8 This is well fitting with the observation that the time point of initial collagen upregulation in the dibutyltin dichloride model coincides with that where monocyte infiltration is first detected, further suggesting that inflammatory cells are a major driving force of the fibrogenic response.9

If induction of fibrogenesis by infiltrating monocytes cells is certainly a major mechanism underlying the effects of anti-MCP-1 therapy, it should be considered that inflammatory cells and fibrogenic myofibroblasts have a “bidirectional” relationship. Similar to their liver, kidney, or vascular counterparts, activated PSCs have the ability to secrete chemokines, and notably MCP-1, that contribute to local amplification of the inflammatory response.12 Along these lines, proinflammatory stimuli are very active in induction of MCP-1 secretion by PSCs, suggesting that initial inflammation is likely to be maintained after activation of PSCs and the resulting induction of chemokine expression. Amplification of local inflammation is also the result of MCP-1 expression by infiltrating monocytes, as previously demonstrated in specimens obtained in patients with chronic pancreatitis.6 These considerations contribute to explain why, in rats treated with (1, 9–76) MCP-1, a decrease in MCP-1 expression accompanied reduced monocyte infiltration and fibrogenesis.

Accumulating evidence that fibrogenic cells may be targets of the actions of chemokines identifies an additional level of interaction between inflammation and fibrosis. Activated myofibroblasts respond to MCP-1 with chemotaxis and other biological functions, including upregulation of transforming growth factor β1.13 Interestingly, MCP-1 has been shown to modulate the biology of myofibroblastic cells via CCR2 dependent and independent mechanisms, suggesting the existence of an alternative receptor in this cell type.14,15 It is intriguing to observe that in chronic pancreatitis, MCP-1 expression occurs at the edge between acini and fibrotic tissue, a pattern that closely resembles that observed during active fibrogenesis in chronic viral hepatitis.16 These in vivo data, together with the observation of biological actions towards matrix producing cells, indicate the critical role of chemokines as a system contributing to colocalise inflammation and tissue repair.17

Although the mechanisms discussed above appear to be sufficient to explain the effects of anti-MCP-1 gene therapy, the possible involvement of additional factors should not be overlooked. The molecular basis underlying the inhibitory action of (1, 9–76) MCP-1 is still controversial. This molecule may interact with MCP-1 in a dominant negative fashion10 or act as a competitive CCR2 inhibitor.18 It should be kept in mind that CCR2 is a high affinity receptor for chemokines other than MCP-1, and it is possible that some of the effects of the mutated chemokine depend on interference with different chemokine systems. An additional issue is related to the fact that human (1, 9–76) MCP-1 was used in a rat model, because changes in the binding affinity profile may be observed across species.

An intriguing point is also the possibility that (1, 9–76) MCP-1 modulates the biology of cells other than monocytes and/or PSCs. In chronic pancreatitis, a T cell infiltrate is commonly observed, and it is conceivable that quantitative or qualitative changes in T cell infiltrate could have an impact on the development of fibrosis. In fact, a Th2 dominated response has been associated with a higher tendency towards the development of fibrosis in different conditions of tissue injury.19 MCP-1 has been shown to shift the balance of the immune response towards a predominant Th2 phenotype, although surprisingly genetic deletion studies indicate that CCR2 has opposite effects.20,21 Angiogenesis is an additional aspect that could potentially be regulated by MCP-1 in the setting of chronic tissue damage. Generation of newly formed blood vessels is an important feature of the process of tissue repair, and interfering with angiogenesis may limit scarring. Several chemokines have been shown to modulate angiogenesis, in a positive or negative fashion, and MCP-1 is associated with induction of neovessel formation.22 This may represent an additional level at which anti-MCP-1 therapies may prevent fibrosis. Along these lines, it has been recently shown that a subset of endothelial progenitor cells acquire the ability to adhere on injured endothelium in a MCP-1 dependent manner, leading to re-endothelialisation associated with inhibition of intimal hyperplasia.23 These exciting and novel aspects of MCP-1 biology deserve further experimental evaluation in conditions of fibrosis.

The paper published in this issue of Gut provides a convincing proof of concept that modulating MCP-1 may be an additional approach to limit the progression of chronic pancreatitis.8 However, it is still uncertain to what extent these approaches may be applicable to the human situation. A strategy like the one used by Zhao and colleagues,8 with intramuscular injection of naked DNA, has been proposed in humans for vaccination. The possibility of inducing an immune response against the molecule encoded by the injected plasmid may, on one hand, strengthen the therapeutic response if the target is wild-type MCP-1, but on the other hand, the possibility of an immune response involving autoantigens in common with the mutated chemokine should be considered. Chemokine receptors belong to class A G protein coupled receptors, which can theoretically be inhibited by small molecule antagonists.24 A small orally available inhibitor of the actions of MCP-1 appears to be the most appealing prospect for conditions such as chronic pancreatitis that require long term treatment. We anticipate fast development in this area, and look forward to the availability of a new armamentarium of drugs effective in the treatment of chronic inflammatory and fibrogenic diseases.

Note added in proofs: After submission of this commentary, Papachristou et al reported that patients with severe acute pancreatitis have a significantly greater proportion of the MCP-1 -2518G allele, which is associated with increased MCP-1 in response to inflammatory stimuli, than patients with mild acute pancreatitis.25


Work in Dr Marra’s laboratory is supported by grants from the Italian MIUR, the University of Florence, and the Italian Liver Foundation.

Evidence of a mechanistic role for monocyte chemoattractant protein 1 (MCP-1) in the pathogenesis of inflammation and fibrosis associated with experimental pancreatitis


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  • Conflict of interest: None declared.

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