PERSPECTIVE
Interleukin-10
The Missing Link in Asthma Regulation?

Dale T. Umetsu and Rosemarie H. DeKruyff

Department of Pediatrics, Center for Asthma and Allergic Diseases, and Division of Immunology and Transplantation Biology, Stanford University, Stanford, California

Much experimental work in the past decade has been directed at explaining the inflammatory processes that occur in the lungs of patients with asthma. Eosinophils, basophils, mast cells, and immunoglobulin (Ig)E play prominent pathologic roles in asthma. Furthermore, T-helper (Th)2 lymphocytes secrete interleukin (IL)-4, IL-5, and IL-13, and induce, prolong, and amplify the inflammatory response by enhancing the production of IgE; enhancing the recruitment, growth, and differentiation of eosinophils, and directly causing airway hyperreactivity. Therapies for asthma understandably focus on neutralizing these inflammatory factors and eliminating eosinophils, lymphocytes, and IgE.

While the task of neutralizing all aspects of the inflammatory processes in asthma is difficult with the medical therapies currently available, elimination of inflammation occurs successfully on a daily basis in the lungs of those who do not have asthma. The specific mechanisms that prevent the development of asthmatic inflammation in the lungs of normal individuals, however, are poorly understood. Many have assumed that because Th2 cells are pathogenic for asthma, the "opposite" cell type (i.e., the Th1 cell), plays a major role in protection against allergic disease and asthma. Is this really true?

In this issue, Stämpfli and coworkers suggest that IL-10, a cytokine with potent anti-inflammatory and immunoregulatory activityrather than Th1-related cytokineseffectively inhibits the development of airway inflammation (1). They demonstrated that administration of IL-10 into the lungs, using replication-deficient adenovirus vectors in a murine model of airway hyperreactivity during the time of mucosal sensitization, abrogated both the cellular and physiologic recall responses in vivo. The prevention of airway eosinophilia by IL-10 was independent of interferon- (IFN-) and was associated with decreased production of IL-4, IL-5, and tumor necrosis factor- (TNF-) in the lungs. Thus, these authors suggest that IL-10 is a critical regulatory molecule involved in the prevention of asthma.

Conventional wisdom of immunologists studying T cells in asthma says that asthma is a Th2 disease, in which lack of Th1-cytokine production results in excess Th2-cytokine production and in disease pathology (2). There is much experimental evidence to support the assumption that Th1 cytokines counterbalance Th2 cells; however, this evidence has been developed primarily in infectious disease models. For example, in models of Leishmania infection, Th1 cells, which are responsible for protective immunity against this pathogen, inhibit the development of detrimental Th2 responses that cause dissemination of the infection. In addition, epidemiologic data demonstrate that individuals predisposed toward the production of Th1 cytokines (e.g., those infected with Mycobacteria tuberculosis or patients with multiple sclerosis) have a reduced likelihood of developing allergic disease and asthma (3, 4). Furthermore, studies concerning allergen immunotherapy in humans (5- 7), administration of IL-12 or IL-12-fusion proteins, or plasmids containing complementary DNA (cDNA) for allergens (8) together suggest that replacing allergen-specific Th2 cells with Th1 cells, which counterbalance the pathologic effects of Th2 cells, protects against asthma.

If Th1 cells, however, really counterbalance Th2 cells in the airway, then one would predict that Th1 cells would be prominent in the lungs of normal, nonasthmatic patients. This does not appear to be the case. The lungs of healthy people have very few lymphocytes, suggesting that other mechanisms are important in downregulating and preventing asthmatic symptoms in nonasthmatic persons. Moreover, the presence of large numbers of Th1-effector cells in the lung is associated with a tissue-damaging inflammatory response. For example, activated Th1 cells in the lung produce acute, neutrophilic airway inflammation and fail to inhibit Th2-cell-induced airway hyperreactivity (12). In addition, studies with Th1 and Th2 cells in autoimmune encephalomyelitis and diabetes mellitus indicate that Th1 and Th2 cells may not always antagonize each other, and that polarized Th2 cells, which are generally assumed to be protective in autoimmunity, may in some instances be unexpectedly harmful (16). Together, these studies indicate that the regulation of asthma and allergic disease may not be reflected in a simple, dichotomous balance of polarized cells, as suggested by the Th1/Th2 paradigm, and that Th1 cells may not be as beneficial in asthma as initially thought.

The studies by Stämpfli and coworkers suggest that IL-10 may provide the mechanism by which allergic inflammatory processes in the lungs are downregulated. IL-10 can inhibit airway inflammation by reducing inflammatory cytokine and chemokine production and by inhibiting antigen presentation to T cells by limiting class II CD80 (B7.1)- and CD86 (B7.2)-expression on antigen-presenting cells (19). Indeed, the absence of IL-10 (e.g., in IL-10-gene knockout mice) results in severe allergen-induced airway inflammation with exaggerated production of IL-4, IL-5, and IFN- compared with that of wild-type mice. Consistent with this idea is the observation that significantly less IL-10 is found in the lungs of patients with asthma (19, 20). Thus, the normal production of IL-10 in the lungs of nonasthmatic people may be responsible for limiting inflammatory Th2-like processes.

The idea that reduced IL-10 production may significantly contribute to the inflammatory response in asthma is also consistent with other studies that examine mucosal immunity. Much can be learned from comparing mucosal immunity and inflammation in the lung with that in the gastrointestinal tract. In the gut, IL-10 as well as transforming growth factor- (TGF-) play important roles in downregulating pathologic inflammation induced by both Th1 and Th2 cells. Although Th1 cells may inhibit the development of Th2 cells from naive cells in peripheral lymphoid organs, such as the spleen and lymph nodes, and thus potentially be of some benefit in treating asthma, the localization of Th1 cells into such mucosal tissues is associated with pathologic processes (e.g., sarcoidosis or inflammatory bowel disease). On the other hand, the production of high levels of IL-10 in the lungs may significantly inhibit airway inflammation without causing parenchymal damage and may indeed be what is missing in patients with asthma.

Although the scenario with IL-10 proposed by Stämpfli and coworkers has attractive features, the picture is far from clear. For example, does IL-10 have direct inhibitory effects on T cells and epithelial cells or does IL-10 induce additional regulatory cells such as Tr1 cells? (21) Are monocytes and B cells, the major producers of IL-10 in humans, deficient in producing IL-10 in patients with asthma or is low production of IL-10 secondary to other processes? Moreover, can the administration of IL-10 to patients with asthma reverse ongoing airway hyperreactivity and inflammation? Having the answers to these questions is critical before administration of IL-10 can be advocated in patients with asthma. Yet despite these limitations, it is very likely that IL-10 plays an important biologic role in asthma and that further important studies characterizing this molecule's activity in asthma are required. The difficulty in studying the effects of IL-10 is that IL-10 eliminates inflammation, and the absence of inflammation is difficult to study, thus possibly explaining why focus on IL-10 as a regulatory molecule in asthmatic airway inflammation has been limited in the past.

	Footnotes

Address correspondence to: Dale T. Umetsu, M.D., Ph.D., Dept. of Pediatrics, Rm. H307, Stanford University, Stanford, CA 34305-5208.

(Received in original form August 2, 1999).

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